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<script type="text/javascript" src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.boots.min.js"> </script><title>Screen for RAS-Selective Lethal Compounds and VDAC Ligands - Probe 1 - Probe Reports from the NIH Molecular Libraries Program - NCBI Bookshelf</title>
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<meta name="citation_inbook_title" content="Probe Reports from the NIH Molecular Libraries Program [Internet]">
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<meta name="citation_title" content="Screen for RAS-Selective Lethal Compounds and VDAC Ligands - Probe 1">
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<meta name="citation_publisher" content="National Center for Biotechnology Information (US)">
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<meta name="citation_date" content="2011/02/10">
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<meta name="citation_author" content="Joshua A Bittker">
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<meta name="citation_author" content="Michel Weiwer">
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<meta name="citation_author" content="Kenichi Shimada">
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<meta name="citation_author" content="Wan S Yang">
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<meta name="citation_author" content="Lawrence MacPherson">
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<meta name="citation_author" content="Sivaraman Dandapani">
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<meta name="citation_author" content="Ben Munoz">
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<meta name="citation_author" content="Michelle Palmer">
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<meta name="citation_author" content="Brent R Stockwell">
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<meta name="citation_author" content="Stuart L Schreiber">
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<meta name="citation_pmid" content="21634081">
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<meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK55069/">
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<meta name="DC.Title" content="Screen for RAS-Selective Lethal Compounds and VDAC Ligands - Probe 1">
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<meta name="DC.Publisher" content="National Center for Biotechnology Information (US)">
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<meta name="DC.Contributor" content="Joshua A Bittker">
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<meta name="DC.Contributor" content="Michel Weiwer">
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<meta name="DC.Contributor" content="Kenichi Shimada">
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<meta name="DC.Contributor" content="Wan S Yang">
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<meta name="DC.Contributor" content="Lawrence MacPherson">
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<meta name="DC.Contributor" content="Sivaraman Dandapani">
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<meta name="DC.Contributor" content="Ben Munoz">
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<meta name="DC.Contributor" content="Michelle Palmer">
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<meta name="DC.Contributor" content="Brent R Stockwell">
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<meta name="DC.Contributor" content="Stuart L Schreiber">
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<meta name="DC.Date" content="2011/02/10">
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<meta name="description" content="Synthetic lethal screening is a chemical biology approach to identify small molecules that selectively kill oncogene-expressing engineered cell lines, with the goal of identifying pathways that provide specific targets against cancer cells. We performed a high-throughput screen of 303,282 compounds from the Molecular Libraries Small Molecule Repository (MLSMR) against immortalized BJ fibroblasts expressing HRasV12 followed by a counterscreen of lethal compounds in a series of isogenic cells lacking the oncogene. A chemical class was identified that had improved potency and specificity compared to previously known selective compounds. The most potent and selective of these, probe CID 3689413/ML162, displayed nanomolar potency in the primary screening cell line. Despite an essential common reactive group in the probe and analogs, significant selective lethality has been observed in the engineered as well as other cell lines. This probe will, therefore, be highly useful in identifying pathways that can potentially be used for selectively inhibiting cancer cells.">
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<meta name="og:description" content="Synthetic lethal screening is a chemical biology approach to identify small molecules that selectively kill oncogene-expressing engineered cell lines, with the goal of identifying pathways that provide specific targets against cancer cells. We performed a high-throughput screen of 303,282 compounds from the Molecular Libraries Small Molecule Repository (MLSMR) against immortalized BJ fibroblasts expressing HRasV12 followed by a counterscreen of lethal compounds in a series of isogenic cells lacking the oncogene. A chemical class was identified that had improved potency and specificity compared to previously known selective compounds. The most potent and selective of these, probe CID 3689413/ML162, displayed nanomolar potency in the primary screening cell line. Despite an essential common reactive group in the probe and analogs, significant selective lethality has been observed in the engineered as well as other cell lines. This probe will, therefore, be highly useful in identifying pathways that can potentially be used for selectively inhibiting cancer cells.">
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id="jr-fip-info-p"><a id="jr-fip-prev" class="wsprkl btn" title="Jump to previuos match">◀</a><button id="jr-fip-matches">no matches yet</button><a id="jr-fip-next" class="wsprkl btn" title="Jump to next match">▶</a></nav></nav></div><div id="jr-epub-interstitial" class="hidden"></div><div id="jr-content"><article data-type="main"><div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><div class="fm-sec"><h1 id="_NBK55069_"><span class="title" itemprop="name">Screen for RAS-Selective Lethal Compounds and VDAC Ligands - Probe 1</span></h1><p class="contribs">Bittker JA, Weiwer M, Shimada K, et al.</p><p class="fm-aai"><a href="#_NBK55069_pubdet_">Publication Details</a></p></div></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="_abs_rndgid_" itemprop="description"><p>Synthetic lethal screening is a chemical biology approach to identify small molecules that selectively kill oncogene-expressing engineered cell lines, with the goal of identifying pathways that provide specific targets against cancer cells. We performed a high-throughput screen of 303,282 compounds from the Molecular Libraries Small Molecule Repository (MLSMR) against immortalized BJ fibroblasts expressing HRas<sup>V12</sup> followed by a counterscreen of lethal compounds in a series of isogenic cells lacking the oncogene. A chemical class was identified that had improved potency and specificity compared to previously known selective compounds. The most potent and selective of these, probe CID 3689413/<a href="/pcsubstance/?term=ML162[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML162</a>, displayed nanomolar potency in the primary screening cell line. Despite an essential common reactive group in the probe and analogs, significant selective lethality has been observed in the engineered as well as other cell lines. This probe will, therefore, be highly useful in identifying pathways that can potentially be used for selectively inhibiting cancer cells.</p></div><div class="h2"></div><p><b>Assigned Assay Grant #:</b> 1R03MH084117-01</p><p><b>Screening Center Name & PI:</b> Broad Institute Probe Development Center, Stuart Schreiber</p><p><b>Chemistry Center Name & PI:</b> Broad Institute Probe Development Center, Stuart Schreiber</p><p><b>Assay Submitter & Institution:</b> Brent R. Stockwell, Howard Hughes Medical Institute, Columbia University</p><p><b>PubChem Summary Bioassay Identifier (AID):</b>
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<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1674" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 1674</a></p><div id="ml162.s1"><h2 id="_ml162_s1_">Probe Structure & Characteristics</h2><div id="ml162.fu1" class="figure"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu1.jpg" alt="Image ml162fu1" /></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml162tu1"><a href="/books/NBK55069/table/ml162.tu1/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figml162tu1" rid-ob="figobml162tu1"><img class="small-thumb" src="/books/NBK55069/table/ml162.tu1/?report=thumb" src-large="/books/NBK55069/table/ml162.tu1/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ml162.tu1"><a href="/books/NBK55069/table/ml162.tu1/?report=objectonly" target="object" rid-ob="figobml162tu1">Table</a></h4></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml162tu2"><a href="/books/NBK55069/table/ml162.tu2/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figml162tu2" rid-ob="figobml162tu2"><img class="small-thumb" src="/books/NBK55069/table/ml162.tu2/?report=thumb" src-large="/books/NBK55069/table/ml162.tu2/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ml162.tu2"><a href="/books/NBK55069/table/ml162.tu2/?report=objectonly" target="object" rid-ob="figobml162tu2">Table</a></h4></div></div></div><div id="ml162.s2"><h2 id="_ml162_s2_">Recommendations for scientific use of the probe</h2><p>The goal of the project is to identify small molecules that are selectively lethal to tumor cells expressing RAS oncogenes. These probes will not necessarily interact with the RAS pathway, but may induce cell death by affecting cellular processes that, in conjunction with the activation of the RAS pathway, selectively kill the tumor cells.</p><p>One goal of identifying novel RAS selective probes is to determine additional pathways that may be targets for novel therapeutics. All three existing probes result in the same phenotype, with two of the three having confirmed activity against the same target, voltage-dependent anion channels (VDACs.) Additional probes against other targets will assist in elucidating other targets or pathways of interest in RAS dependent tumors. In addition, novel probes that are similar to existing compounds that do target VDACs, but which have different selectivity or binding modes, will be valuable in determining the potential use of VDAC inhibition as a therapeutic method.</p><p>The probe CID 3689413/<a href="/pcsubstance/?term=ML162[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML162</a> described herein has structural and biological properties similar to a previously known compound (RSL3) but has improved selectivity and potency. This probe, therefore, represents an improvement over the state of the art (see <a href="#ml162.s29">Section 4.1</a>, <a class="figpopup" href="/books/NBK55069/table/ml162.t2/?report=objectonly" target="object" rid-figpopup="figml162t2" rid-ob="figobml162t2">Table 2</a>), and will be of benefit to the scientific community in determining the effects of RAS mutation on cellular pathways.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml162t2"><a href="/books/NBK55069/table/ml162.t2/?report=objectonly" target="object" title="Table 2" class="img_link icnblk_img figpopup" rid-figpopup="figml162t2" rid-ob="figobml162t2"><img class="small-thumb" src="/books/NBK55069/table/ml162.t2/?report=thumb" src-large="/books/NBK55069/table/ml162.t2/?report=previmg" alt="Table 2. Summary of SAR on the Aniline Aromatic Ring." /></a><div class="icnblk_cntnt"><h4 id="ml162.t2"><a href="/books/NBK55069/table/ml162.t2/?report=objectonly" target="object" rid-ob="figobml162t2">Table 2</a></h4><p class="float-caption no_bottom_margin">Summary of SAR on the Aniline Aromatic Ring. </p></div></div></div><div id="ml162.s3"><h2 id="_ml162_s3_">1. Introduction</h2><p>The first rat sarcoma (RAS) oncogene was discovered as a genetic element from the Harvey and Kirsten rat sarcoma viruses with the ability to immortalize mammalian cells (<a class="bibr" href="#ml162.r1" rid="ml162.r1">1</a>,<a class="bibr" href="#ml162.r2" rid="ml162.r2">2</a>,<a class="bibr" href="#ml162.r3" rid="ml162.r3">3</a>). Mutated RAS oncogenes (i.e., HRAS, NRAS, and KRAS) are found in 10–20% of all human cancer. KRAS mutations are found in >90% of pancreatic cancers, 50% of colon cancers, and 25% of lung adenocarcinomas; NRAS mutations are found in 30% of liver cancers and 15% of melanomas; and HRAS mutations are found in 10% of kidney and bladder cancers (<a class="bibr" href="#ml162.r4" rid="ml162.r4">4</a>).</p><p>RAS proteins are guanine-nucleotide-binding proteins with GTPase activity and are associated with the plasma membrane. In the GTP-bound form, RAS proteins are mitogenic. Mutation of glycine-12 to other amino acids (including valine [RASG12V]) results in an oncogenic allele with constitutive mitogenic, transforming activity and reduced GTPase activity (<a class="bibr" href="#ml162.r5" rid="ml162.r5">5</a>). Four downstream pathways activated by RAS proteins are: 1) the RAF/MEK/ERK pathway, which regulates cell-cycle progression, 2) the PI3K/PDK/AKT pathway, which regulates cell survival, 3) the RalGDS pathway, which regulates membrane trafficking and vesicle formation, and 4) the PLCɛ/PKC pathway, which regulates Ca<sup>++</sup> signaling (<a class="bibr" href="#ml162.r5" rid="ml162.r5">5</a>,<a class="bibr" href="#ml162.r6" rid="ml162.r6">6</a>,<a class="bibr" href="#ml162.r7" rid="ml162.r7">7</a>).</p><p>Compounds that selectively kill cells expressing oncogenic RAS have the potential to eliminate tumor cells harboring specific oncogenic mutations while having minimal effects on normal cells lacking these mutations. This mode of action is known as synthetic lethality. Such synthetically lethal compounds can be used to elucidate the pathways that are involved in the oncogenesis of the mutant RAS gene whether directly in RAS-related pathways or in other pathways, such as metabolic function, that may be modulated by the activity of an oncogenic allele.</p><p>RAS synthetic lethal genes (such as TBK1, CCNA2, KIF2C, PLK1, APC/C, CDK4, and STK33) have recently been identified using RNAi screens (<a class="bibr" href="#ml162.r8" rid="ml162.r8">8</a>,<a class="bibr" href="#ml162.r9" rid="ml162.r9">9</a>,<a class="bibr" href="#ml162.r10" rid="ml162.r10">10</a>,<a class="bibr" href="#ml162.r11" rid="ml162.r11">11</a>,<a class="bibr" href="#ml162.r12" rid="ml162.r12">12</a>). Efforts were then undertaken to develop small molecule inhibitors of these targets, especially kinases. BI 6727, a PLK1 inhibitor developed by Boehringer Ingelheim (<a class="bibr" href="#ml162.r13" rid="ml162.r13">13</a>), BX 795, a TBK1 inhibitor developed by Berlex Biosciences (<a class="bibr" href="#ml162.r14" rid="ml162.r14">14</a>), and PD 0332991, a CDK4 inhibitor developed by Pfizer (<a class="bibr" href="#ml162.r15" rid="ml162.r15">15</a>), are presented in <a class="figpopup" href="/books/NBK55069/figure/ml162.f1/?report=objectonly" target="object" rid-figpopup="figml162f1" rid-ob="figobml162f1">Figure 1</a>.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml162f1" co-legend-rid="figlgndml162f1"><a href="/books/NBK55069/figure/ml162.f1/?report=objectonly" target="object" title="Figure 1" class="img_link icnblk_img figpopup" rid-figpopup="figml162f1" rid-ob="figobml162f1"><img class="small-thumb" src="/books/NBK55069/bin/ml162f1.gif" src-large="/books/NBK55069/bin/ml162f1.jpg" alt="Figure 1. RAS Synthetic Lethal Compounds Discovered Through RNAi Screens." /></a><div class="icnblk_cntnt" id="figlgndml162f1"><h4 id="ml162.f1"><a href="/books/NBK55069/figure/ml162.f1/?report=objectonly" target="object" rid-ob="figobml162f1">Figure 1</a></h4><p class="float-caption no_bottom_margin">RAS Synthetic Lethal Compounds Discovered Through RNAi Screens. BI 6727, a PLK1 inhibitor (Boehringer Ingelheim)(<i>a</i>); BX 795, a TBK1 inhibitor (Berlex Biosciences) (<i>b</i>); PD 0332991, a CDK4 inhibitor (Pfizer) (<i>c</i>). </p></div></div><p>In another approach, phenotypic screens allow the direct identification of small molecules that are selectively lethal to cell lines expressing a RAS oncogene. Further studies are then necessary to identify the target. Recently, Guo and colleagues (<a class="bibr" href="#ml162.r16" rid="ml162.r16">16</a>) have described a compound named oncrasin-1 (<a class="figpopup" href="/books/NBK55069/figure/ml162.f2/?report=objectonly" target="object" rid-figpopup="figml162f2" rid-ob="figobml162f2">Figure 2a</a>), which is synthetically lethal to cell lines harboring a K-RAS oncogene but ineffective in H-RAS mutant cell lines. Stockwell and colleagues (<a class="bibr" href="#ml162.r17" rid="ml162.r17">17</a>,<a class="bibr" href="#ml162.r18" rid="ml162.r18">18</a>) have identified small molecules that are synthetically lethal to several H-RAS and K-RAS mutant cell lines (<a class="figpopup" href="/books/NBK55069/figure/ml162.f2/?report=objectonly" target="object" rid-figpopup="figml162f2" rid-ob="figobml162f2">Figure 2b</a>). They induce an oxidative, nonapoptotic cell death by targeting the RAS-Raf-MEK pathway. Erastin and RSL5 have been shown to bind to voltage dependent anion channels (VDAC) as opposed to RSL3, which act in a VDAC-independent manner.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml162f2" co-legend-rid="figlgndml162f2"><a href="/books/NBK55069/figure/ml162.f2/?report=objectonly" target="object" title="Figure 2" class="img_link icnblk_img figpopup" rid-figpopup="figml162f2" rid-ob="figobml162f2"><img class="small-thumb" src="/books/NBK55069/bin/ml162f2.gif" src-large="/books/NBK55069/bin/ml162f2.jpg" alt="Figure 2. RAS Synthetic Lethal Compounds Discovered Through Phenotypic Screens." /></a><div class="icnblk_cntnt" id="figlgndml162f2"><h4 id="ml162.f2"><a href="/books/NBK55069/figure/ml162.f2/?report=objectonly" target="object" rid-ob="figobml162f2">Figure 2</a></h4><p class="float-caption no_bottom_margin">RAS Synthetic Lethal Compounds Discovered Through Phenotypic Screens. Compound identified by Guo and colleagues that is synthetically lethal to K-RAS mutant cell lines (<i>a</i>); Compound previously identified by the Stockwell and colleagues that is synthetically <a href="/books/NBK55069/figure/ml162.f2/?report=objectonly" target="object" rid-ob="figobml162f2">(more...)</a></p></div></div><p>While erastin and RSL3 compounds were used as on-target positive controls through this project (<a class="figpopup" href="/books/NBK55069/figure/ml162.f3/?report=objectonly" target="object" rid-figpopup="figml162f3" rid-ob="figobml162f3">Figure 3</a>, <a class="figpopup" href="/books/NBK55069/figure/ml162.f4/?report=objectonly" target="object" rid-figpopup="figml162f4" rid-ob="figobml162f4">Figure 4</a>), additional compounds that produce the same phenotype would be useful in determining alternate modes of binding to VDACs. Other compounds that are synthetically lethal with HRAS<sup>V12</sup>, regardless of mechanism, would be beneficial for identifying additional targets for possible therapeutic intervention.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml162f3" co-legend-rid="figlgndml162f3"><a href="/books/NBK55069/figure/ml162.f3/?report=objectonly" target="object" title="Figure 3" class="img_link icnblk_img figpopup" rid-figpopup="figml162f3" rid-ob="figobml162f3"><img class="small-thumb" src="/books/NBK55069/bin/ml162f3.gif" src-large="/books/NBK55069/bin/ml162f3.jpg" alt="Figure 3. Growth Inhibition of HRASV12 Expressing and Non-expressing Cell Lines by the Positive Control Compound Erastin (CID 11214940) Identified in Pilot Screening." /></a><div class="icnblk_cntnt" id="figlgndml162f3"><h4 id="ml162.f3"><a href="/books/NBK55069/figure/ml162.f3/?report=objectonly" target="object" rid-ob="figobml162f3">Figure 3</a></h4><p class="float-caption no_bottom_margin">Growth Inhibition of HRAS<sup>V12</sup> Expressing and Non-expressing Cell Lines by the Positive Control Compound Erastin (CID 11214940) Identified in Pilot Screening. Growth inhibition concentration-response curves of erastin in engineered BJ fibroblasts expressing <a href="/books/NBK55069/figure/ml162.f3/?report=objectonly" target="object" rid-ob="figobml162f3">(more...)</a></p></div></div><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml162f4" co-legend-rid="figlgndml162f4"><a href="/books/NBK55069/figure/ml162.f4/?report=objectonly" target="object" title="Figure 4" class="img_link icnblk_img figpopup" rid-figpopup="figml162f4" rid-ob="figobml162f4"><img class="small-thumb" src="/books/NBK55069/bin/ml162f4.gif" src-large="/books/NBK55069/bin/ml162f4.jpg" alt="Figure 4. Growth Inhibition of HRASV12 Expressing and Non-expressing Cell Lines by the Positive Control Compound RSL3 (CID 40911229) Identified in Pilot Screening." /></a><div class="icnblk_cntnt" id="figlgndml162f4"><h4 id="ml162.f4"><a href="/books/NBK55069/figure/ml162.f4/?report=objectonly" target="object" rid-ob="figobml162f4">Figure 4</a></h4><p class="float-caption no_bottom_margin">Growth Inhibition of HRAS<sup>V12</sup> Expressing and Non-expressing Cell Lines by the Positive Control Compound RSL3 (CID 40911229) Identified in Pilot Screening. Growth inhibition concentration-response curves of RSL3 in engineered BJ fibroblasts expressing oncogenic <a href="/books/NBK55069/figure/ml162.f4/?report=objectonly" target="object" rid-ob="figobml162f4">(more...)</a></p></div></div></div><div id="ml162.s4"><h2 id="_ml162_s4_">2. Materials and Methods</h2><div id="ml162.s5"><h3>Materials and Reagents</h3><p>All reagents and solvents were purchased from commercial vendors and used as received.</p><p>Phosphate-buffered saline (PBS; catalog no. 08J07A0022) was acquired from the Broad Institute Supply and Quality Management (SQM; Cambridge, MA). CellTiter Glo (catalog no. G7573 lot 268563) was purchased from Promega (Fitchburg, WI), and Alamar Blue (catalog no. DAL1025) was acquired from Biosource/Invitrogen (Grand Island, NY). White, sterile, TC-treated, 384-well plates (catalog no.3570) were acquired from Corning.</p><div id="ml162.s6"><h4>Growth Medium</h4><p>Dulbecco’s modified Eagle’s medium (DMEM; catalog no. 11995, Lot no. 476124) with 4 mM L-glutamine and fetal bovine serum (FBS; catalog no. 26140-079, Lot no. 302496) were purchased from Gibco (Grand Island, NY). M199 (catalog no. M7528, Lot no. 028K2403) was acquired from Sigma (St. Louis, MO). Trypsin (catalog no. 25-053-Cl; Lot no. 25053204) was purchased from MediaTech (Manassas VA).</p></div><div id="ml162.s7"><h4>Cell Lines</h4><p>Throughout the project, four different cell types derived from BJ human fibroblasts were used to determine the effect of compounds on either HRAS<sup>V12</sup>-expressing or wild-type cell lines. The progenitor line was engineered into immortalized tumor lines by the method of Hahn (<a class="bibr" href="#ml162.r20" rid="ml162.r20">20</a>,<a class="bibr" href="#ml162.r21" rid="ml162.r21">21</a>,<a class="bibr" href="#ml162.r22" rid="ml162.r22">22</a>,<a class="bibr" href="#ml162.r23" rid="ml162.r23">23</a>,<a class="bibr" href="#ml162.r24" rid="ml162.r24">24</a>), which uses the expression of human telomerase (hTERT) and the Simian Virus 40 (SV40) large T (LT) and small T (ST) oncoproteins.</p><p>Three versions of these cells were used for screening. The primary screen was performed in fully transformed cells also expressing an oncogenic RAS allele, HRAS<sup>V12</sup>, a line referred to herein as BJeLR. For counterscreening, the isogenic cell line without HRAS<sup>V12</sup> was used, referred to as BJeH-LT. BJ fibroblasts with only hTERT expression were also used for non-HRAS<sup>V12</sup>-expressing counterscreening (BJeH). In addition, an alternative HRAS<sup>V12</sup>-expressing line was generated with different immortalizing factors to eliminate the possibility of compounds acting in a synthetically lethal manner with one of these other factors. These cells (referred to as DRD) are BJ fibroblasts expressing hTERT, SV40 small T oncoprotein, dominant negative p53, cyclin D1, and a mutant form of CDK4, along with the gene of interest, HRAS<sup>V12</sup>.</p></div></div><div id="ml162.s8"><h3>2.1. Assays</h3><p>A summary listing of completed assays and corresponding PubChem AID numbers is provided in <a href="#ml162.app1">Appendix A</a> (<a class="figpopup" href="/books/NBK55069/table/ml162.t7/?report=objectonly" target="object" rid-figpopup="figml162t7" rid-ob="figobml162t7">Table A1</a>). Refer to <a href="#ml162.app2">Appendix B</a> for the detailed assay protocols.</p><div id="ml162.s9"><h4>2.1.1. Primary Screen for BJeLR Cell Viability</h4><p>All cell lines were generated by the Stockwell lab as described previously (<a class="bibr" href="#ml162.r17" rid="ml162.r17">17</a>,<a class="bibr" href="#ml162.r18" rid="ml162.r18">18</a>). Cells were maintained in 35 mL of growth medium (per 1 Liter: 730 ml DMEM with 4 mM L-glutamine, 210 ml M199, 150 ml heat-inactivated fetal bovine serum (FBS) in a T175 cell culture flask (Corning) and incubated in a TC incubator (Thermo-Fisher) at 95% humidity, 5% CO<sub>2</sub>, 37°C. To passage, cells were harvested by first aspirating the media and rinsing the flask with 10 ml sterile PBS. Next, PBS was aspirated and 5 mL trypsin was added to the flask and incubated for 5 minutes at 22°C. Then 8 mL of growth medium was added to the trypsin to quench the reaction. The cells were resuspended, counted, and 4.5 million cells in approximately 2 mL were transferred to 33 mL fresh growth medium in a new T175 flask. The lines were carried for no more than twenty passages.</p><p>For screening, the cells were harvested, and the concentration was adjusted to 33,000/mL. While gently stirring, cells were dispensed with a Combi multidrop (Thermo-Fisher) by adding 30 μL of suspension per well to white, sterile, TC-treated, 384-well plates (Corning) for a total of 1000 cells per well. The plates were incubated overnight in an automated TC incubator (Liconic) at 95% humidity, 5% CO<sub>2</sub>, 37°C.</p><p>For compound screening, 50 nL or 100 nL of compound were added, depending on the desired final compound concentration, using slotted steel pins (V&P Scientific) on a pin tool (HiRes Biosolutions). The plates were returned to the incubator for 48 hours. To read viability, the cells were removed from the incubator and cooled to room temperature for 30 minutes. Lids were removed, and 30 μL of diluted CellTiter Glo (1:3 dilution with PBS) was added to each with a Combi Multidrop. The plates were incubated for 10 minutes, and luminescence was detected on an Envision (Perkin-Elmer) multimode reader (0.1 seconds per well).</p></div><div id="ml162.s10"><h4>2.1.2. Primary Retest for BJeLR Cell Viability</h4><p>Repeat of primary screen at dose in BJeLR cells using Cell TiterGlo.</p></div><div id="ml162.s11"><h4>2.1.3. Secondary Counter screen for BJeH/LT/ST Cell Viability (Cell TiterGlo)</h4><p>As described in the primary screen in BJeLR cells but using the BJeH/LT/ST cell line.</p></div><div id="ml162.s12"><h4>2.1.4. Secondary Screen for DRD Cell Viability (Cell TiterGlo)</h4><p>As described in the primary screen in BJeLR cells but using the DRD cell line.</p></div><div id="ml162.s13"><h4>2.1.5. Secondary Counter screen for BJeH Cell Viability (Cell TiterGlo)</h4><p>As described in the primary screen in BJeLR cells but using the BJeH cell line.</p></div><div id="ml162.s14"><h4>2.1.6. Secondary Screen for BJeLR Cell Viability (Alamar Blue)</h4><p>The compounds were diluted into growth medium by adding 2 μL of DMSO compound solution to 148 μL of medium and mixing thoroughly. Dilutions were made in 384-well stock plates (Greiner, catalog no. 781270). Concentration-response curves were then made by further diluting this plate in series by adding 75 μL of solution to 75 μL of fresh growth medium, proceeding across the 384-well plate.</p><p>Next, 36 μL of cell suspension at 28,000 cells per well were added to the assay plates (1000 cells/well), and 4 μL of the medium containing the dilution series of compound were added to the cells. The cells were incubated for 48 hours in a TC incubator at 95% humidity, 5% CO<sub>2</sub>, 37°C. To measure viability, 10 μL Alamar Blue solution (50% in growth medium) was added to each well. The cells were incubated for 16 hours, and fluorescence intensity was read (544 nM excitation, 590 nM emission.)</p></div><div id="ml162.s15"><h4>2.1.7. Secondary Screen for BJeH-LT/ST Cell Viability (Alamar Blue)</h4><p>As described in the secondary screen in BJeLR cells but using the BJeH-LT/ST cell line.</p></div><div id="ml162.s16"><h4>2.1.8. Secondary Screen for DRD Cell Viability (Alamar Blue)</h4><p>As described in the secondary screen in BJeLR cells but using the DRD cell line.</p></div><div id="ml162.s17"><h4>2.1.9. Secondary Screen for BJeH Cell Viability (Alamar Blue)</h4><p>As described in the primary screen in BJeLR cells but using the BJeH cell line.</p></div></div><div id="ml162.s18"><h3>2.2. Probe Chemical Characterization</h3><div id="ml162.f9" class="figure bk_fig"><div class="graphic"><img src="/books/NBK55069/bin/ml162f9.jpg" alt="Scheme 1. Synthesis of the Probe." /></div><h3><span class="label">Scheme 1</span><span class="title">Synthesis of the Probe</span></h3></div><p><b>General details.</b> The probe compound (CID 3689413/<a href="/pcsubstance/?term=ML162[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML162</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/substance/87692475" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 87692475</a>, MLS002703080) was prepared in one step using the Ugi 4-component reaction. 3-Chloro-4-methoxyaniline and 2-thiophene-carboxaldehyde were stirred in methanol for 15 minutes to form the imine intermediate before addition of 2-chloroacetic acid and 2-phenethyl isocyanide. Full experimental details and characterization are provided below.</p><p>The solubility of the probe was measured in water and in PBS at room temperature and was found to be 0.9 μM in water and 0.8 μM in PBS.</p><p>The stability of the probe (CID 3689413/<a href="/pcsubstance/?term=ML162[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML162</a>) in PBS (0.1% DMSO) was measured over 48 hours, and the data is shown in <a class="figpopup" href="/books/NBK55069/figure/ml162.f5/?report=objectonly" target="object" rid-figpopup="figml162f5" rid-ob="figobml162f5">Figure 5</a> (blue line). We suspected that poor solubility (and not instability) as the reason behind the dramatic drop in the amount of sample over time. To test this, we added acetonitrile to each well (final concentration 50%) and measured the amount of the probe. Amounts detected after addition of acetonitrile is shown in <a class="figpopup" href="/books/NBK55069/figure/ml162.f5/?report=objectonly" target="object" rid-figpopup="figml162f5" rid-ob="figobml162f5">Figure 5</a> (red line). From these results it can be concluded that the probe is stable in PBS as 89.9% of the probe is still present after 48 hours of incubation in PBS.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml162f5" co-legend-rid="figlgndml162f5"><a href="/books/NBK55069/figure/ml162.f5/?report=objectonly" target="object" title="Figure 5" class="img_link icnblk_img figpopup" rid-figpopup="figml162f5" rid-ob="figobml162f5"><img class="small-thumb" src="/books/NBK55069/bin/ml162f5.gif" src-large="/books/NBK55069/bin/ml162f5.jpg" alt="Figure 5. Stability Data for the Probe (CID 3689413/ML162) in PBS." /></a><div class="icnblk_cntnt" id="figlgndml162f5"><h4 id="ml162.f5"><a href="/books/NBK55069/figure/ml162.f5/?report=objectonly" target="object" rid-ob="figobml162f5">Figure 5</a></h4><p class="float-caption no_bottom_margin">Stability Data for the Probe (CID 3689413/ML162) in PBS. Total ion count of the probe over time in PBS (blue line). Total ion count of the probe upon addition of acetonitrile (red line). </p></div></div><p>The probe (CID 3689413/<a href="/pcsubstance/?term=ML162[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML162</a>), a racemic mixture, was subjected to chiral HPLC separation to investigate the importance of the chiral center on activity and selectivity. Using a Chiralcel OD-H 10*250 mm, 5-μm column (Chiral Technologies, West Chester, PA; catalog no. 14335) with a gradient of methanol in hexane, both enantiomers were obtained with >99% ee and were tested in the cell assays. However, they were shown to have the same activity and selectivity for HRAS mutant cell lines. To establish whether a pure enantiomer can racemize in the assay conditions, one enantiomer was subjected to a PBS stability assay. After, 48 hours of incubation in PBS (0.1% DMSO), the compound was extracted, concentrated, and injected on a chiral HPLC/MS. No detectable racemization could be observed (<a class="figpopup" href="/books/NBK55069/figure/ml162.f6/?report=objectonly" target="object" rid-figpopup="figml162f6" rid-ob="figobml162f6">Figure 6</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml162f6" co-legend-rid="figlgndml162f6"><a href="/books/NBK55069/figure/ml162.f6/?report=objectonly" target="object" title="Figure 6" class="img_link icnblk_img figpopup" rid-figpopup="figml162f6" rid-ob="figobml162f6"><img class="small-thumb" src="/books/NBK55069/bin/ml162f6.gif" src-large="/books/NBK55069/bin/ml162f6.jpg" alt="Figure 6. Racemic Mixture of the Probe (CID 3689413/ML162) in PBS." /></a><div class="icnblk_cntnt" id="figlgndml162f6"><h4 id="ml162.f6"><a href="/books/NBK55069/figure/ml162.f6/?report=objectonly" target="object" rid-ob="figobml162f6">Figure 6</a></h4><p class="float-caption no_bottom_margin">Racemic Mixture of the Probe (CID 3689413/ML162) in PBS. Racemic mixture of the probe (CID 3689413/ML162) (<i>a</i>); single enantiomer A after purification on chiral HPLC (<i>b</i>); single enantiomer B after purification on chiral HPLC (<i>c</i>); and single enantiomer <a href="/books/NBK55069/figure/ml162.f6/?report=objectonly" target="object" rid-ob="figobml162f6">(more...)</a></p></div></div></div><div id="ml162.s19"><h3>2.3. Probe Preparation</h3><p><b>General details.</b> All reagents and solvents were purchased from commercial vendors and used as received. NMR spectra were recorded on a Bruker 300 MHz or Varian UNITY INOVA 500 MHz spectrometer as indicated. Proton and carbon chemical shifts are reported in ppm (δ) relative to tetramethylsilane or CDCl<sub>3</sub> solvent (<sup>1</sup>H δ 7.26, <sup>13</sup>C δ 77.0). NMR data are reported as follows: chemical shifts, multiplicity (obs. = obscured, br = broad, s = singlet, d = doublet, t = triplet, m = multiplet); coupling constant(s) in Hz; integration. Unless otherwise indicated NMR data were collected at 25°C. Flash chromatography was performed using 40–60 μm Silica Gel (60 Å mesh) on a Teledyne Isco Combiflash R<i>f</i> system. Tandem Liquid Chromatography/Mass Spectrometry (LCMS) was performed on a Waters 2795 separations module and 3100 mass detector. Analytical thin layer chromatography (TLC) was performed on EM Reagent 0.25 mm silica gel 60-F plates. Visualization was accomplished with ultraviolet (UV) light and aqueous potassium permanganate (KMnO<sub>4</sub>) stain followed by heating.</p><p><b>2-chloro-N-(3-chloro-4-methoxyphenyl)-N-(2-oxo-2-(phenethylamino)-1-(thiophen-2-yl)ethyl) acetamide:</b> 2-Thiophene carboxaldehyde (51 mg, 0.45 mmol) was dissolved in MeOH (189 μl) and 3-chloro-4-methoxyaniline (71.5 mg, 0.45 mmol) was added. The mixture was stirred for 15 minutes and 2-chloroacetic acid (35.7 mg, 0.38 mmol) and 2-phenethyl isocyanide (50 mg, 0.38 mmol) were added. After stirring at room temperature for 48 hours, the solvents were evaporated. The crude material was purified by column chromatography over silica gel (hexanes/ethyl acetate: 100/0 to 0/100) to afford 106 mg (0.22 mmol, 59% yield) of the probe as a white solid.</p><p><b><sup>1</sup>H NMR (500 MHz, CDCl<sub>3</sub>):</b> δ 7.29–7.13 (m, 7H), 6.90–6.70 (m, 4H), 6.09 (s, 1H), 6.03 (br. s, 1H), 3.89 (s, 3H), 3.82 (s, 2H), 3.60–3.50 (m, 2H), 2.90–2.75 (m, 2H); <b><sup>13</sup>C NMR (125 MHz, CDCl<sub>3</sub>):</b> δ 167.92, 166.71, 155.54, 138.60, 134.80, 130.07, 128.81, 128.59, 128.23, 126.50, 111.73, 60.71, 56.26, 42.25, 41.04, 35.49. <b>HRMS (ESI):</b> calculated mass for C<sub>23</sub>H<sub>21</sub>Cl<sub>2</sub>N<sub>2</sub>O<sub>3</sub>S [M-H]<sup>−</sup> 475.0655, found 475.0669.</p><p>The <sup>1</sup>H NMR and <b><sup>13</sup></b>C spectra and LC-MS chromatograms of the probe (CID 3689413/<a href="/pcsubstance/?term=ML162[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML162</a>) and analogs are provided in <a href="#ml162.app3">Appendix C</a>.</p></div></div><div id="ml162.s20"><h2 id="_ml162_s20_">3. Results</h2><div id="ml162.s21"><h3>Probe Attributes</h3><ul><li class="half_rhythm"><div>Confirmed activity in the RAS-dependent strains <2.5 μM.</div></li><li class="half_rhythm"><div>At least 4-fold weaker IC<sub>50</sub> activity in the non-RAS strains.</div></li></ul><p>The project included a primary high throughput screen of the entire MLSMR collection (greater than 300,000 substances). Approximately 0.4% of the compounds tested were selected for dose retest and selectivity. Of these, 14 compounds from the same chemical class were identified as having the desired selectivity. In addition to these commercially available compounds, multiple rounds of chemistry were performed to determine the SAR of several substituents on the scaffold, and the compound with the best combination of potency and selectivity was designated as the probe (CID 3689413/<a href="/pcsubstance/?term=ML162[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML162</a>).</p></div><div id="ml162.s22"><h3>3.1. Summary of Screening Results</h3><p>A high throughput screen of 303,344 substances (303,282 unique compounds, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1832" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 1832</a>) was performed in duplicate in a 7.5-μL reaction in 384-well plates seeded with 1000 cells per well in DMEM/FBS medium. Cells were grown overnight, then treated with compound at a final concentration of 7.5 μM for 48 hours, after which cell viability was measured through determination of ATP levels using Promega Cell-TiterGlo reagent. Compounds causing at least 50% reduction in ATP levels relative to DMSO-treated cells were considered active. This resulted in 516 active compounds, which were retested at dose along with several analogs of active families for a total of 1155 compounds (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1936" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 1936</a>). These 1155 compounds were counterscreened against BJeH-LT (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1935" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 1935</a>) and BJ-eH (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1933" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 1933</a>) and also confirmed in a secondary assay for mechanism of action in DRD cells (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1934" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 1934</a>.) The compounds that passed these four screens were analyzed by the Assay Provider using a related viability assay in which Alamar Blue was metabolized to a fluorescent product by living cells; however, the same selectivity profiles were not observed in these secondary assays, either due to differences in maintenance of cell lines or due to the different detection methods.</p><p>As a result of this discrepancy, the available most active compounds from the primary screen (435 compounds) were tested in BJeLR (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2610" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2610</a>) and BJeH-LT (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2631" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2631</a>) by the Assay Provider to determine selectivity. Of these, 73 of 435 compounds were then tested in the two additional cell lines: DRD (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2633" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2633</a>) and BJeH (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2635" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2635</a>). Of these compounds, 26 of 73 displayed the desired potency and selectivity in all four assays and were designated as probe candidates. Of these, 14 were commercially available, which were then confirmed in the four cell lines (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2607" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2607</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2608" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2608</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2609" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2609</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2611" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2611</a>; <a class="figpopup" href="/books/NBK55069/table/ml162.t1/?report=objectonly" target="object" rid-figpopup="figml162t1" rid-ob="figobml162t1">Table 1</a> and <a class="figpopup" href="/books/NBK55069/figure/ml162.f7/?report=objectonly" target="object" rid-figpopup="figml162f7" rid-ob="figobml162f7">Figure 7</a>) These 14 probe candidates were in the same chemical class, containing a common chemically reactive “warhead” in the form of an alpha-chloroamide. The candidate with the best combination of potency, selectivity, and chemical tractability was selected as the probe CID 3689413/<a href="/pcsubstance/?term=ML162[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML162</a> (2-(3-chloro-N-(2-chloroacetyl)-4-methoxyanilino)-N-phenethyl-2-thiophen-2-ylacetamide) with the remaining related candidates providing structure-activity relationship data.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml162t1"><a href="/books/NBK55069/table/ml162.t1/?report=objectonly" target="object" title="Table 1" class="img_link icnblk_img figpopup" rid-figpopup="figml162t1" rid-ob="figobml162t1"><img class="small-thumb" src="/books/NBK55069/table/ml162.t1/?report=thumb" src-large="/books/NBK55069/table/ml162.t1/?report=previmg" alt="Table 1. Summary of SAR on the Alpha-Chloroamide Portion." /></a><div class="icnblk_cntnt"><h4 id="ml162.t1"><a href="/books/NBK55069/table/ml162.t1/?report=objectonly" target="object" rid-ob="figobml162t1">Table 1</a></h4><p class="float-caption no_bottom_margin">Summary of SAR on the Alpha-Chloroamide Portion. </p></div></div><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml162f7" co-legend-rid="figlgndml162f7"><a href="/books/NBK55069/figure/ml162.f7/?report=objectonly" target="object" title="Figure 7" class="img_link icnblk_img figpopup" rid-figpopup="figml162f7" rid-ob="figobml162f7"><img class="small-thumb" src="/books/NBK55069/bin/ml162f7.gif" src-large="/books/NBK55069/bin/ml162f7.jpg" alt="Figure 7. Critical Path for Probe Development." /></a><div class="icnblk_cntnt" id="figlgndml162f7"><h4 id="ml162.f7"><a href="/books/NBK55069/figure/ml162.f7/?report=objectonly" target="object" rid-ob="figobml162f7">Figure 7</a></h4><p class="float-caption no_bottom_margin">Critical Path for Probe Development. </p></div></div></div><div id="ml162.s23"><h3>3.2. Dose Response Curves for Probe</h3><p>The inhibition of cell viability curves for the probe (CID 3689413/<a href="/pcsubstance/?term=ML162[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML162</a>) in four different cell lines are displayed in <a class="figpopup" href="/books/NBK55069/figure/ml162.f8/?report=objectonly" target="object" rid-figpopup="figml162f8" rid-ob="figobml162f8">Figure 8</a>.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml162f8" co-legend-rid="figlgndml162f8"><a href="/books/NBK55069/figure/ml162.f8/?report=objectonly" target="object" title="Figure 8" class="img_link icnblk_img figpopup" rid-figpopup="figml162f8" rid-ob="figobml162f8"><img class="small-thumb" src="/books/NBK55069/bin/ml162f8.gif" src-large="/books/NBK55069/bin/ml162f8.jpg" alt="Figure 8. Concentration-dependent Activities by the Probe (CID 3689413/ML162) in HRASV12 Expressing and Non-expressing Cell Lines." /></a><div class="icnblk_cntnt" id="figlgndml162f8"><h4 id="ml162.f8"><a href="/books/NBK55069/figure/ml162.f8/?report=objectonly" target="object" rid-ob="figobml162f8">Figure 8</a></h4><p class="float-caption no_bottom_margin">Concentration-dependent Activities by the Probe (CID 3689413/ML162) in HRAS<sup>V12</sup> Expressing and Non-expressing Cell Lines. Activity curves for probe (CID 3689413/ML162): BJeLR (AID 2608) (<i>a</i>); DRD (AID 2607) (<i>b</i>); BJeH-LT (AID 2609)(<i>c</i>); BJeH (AID 2611)(<i>d</i> <a href="/books/NBK55069/figure/ml162.f8/?report=objectonly" target="object" rid-ob="figobml162f8">(more...)</a></p></div></div></div><div id="ml162.s24"><h3>3.3. Scaffold/Moiety Chemical Liabilities</h3><p>The probe (CID 3689413/<a href="/pcsubstance/?term=ML162[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML162</a>) contains an alpha-chloroamide moiety and could potentially be a nonselective alkylating agent. The functionality was essential for activity and could not be removed despite generation of analogs attempting to do so. Thus, stability of the probe in the presence of glutathione (GSH) was investigated. After 48 hours of incubation of the probe at 10 μM in PBS (0.1% DMSO) at room temperature, in the presence of a physiologically relevant amount of glutathione (5 mM), no trace of the corresponding GSH adduct could be detected. Only the probe was identified, showing both PBS stability and GSH stability of the probe molecule.</p></div><div id="ml162.s25"><h3>3.4. SAR Tables</h3><p>To further investigate the structure activity relationship of the probe, 16 new analogs have been synthesized using the Ugi 4-component reaction. The influence of all four components has been investigated, and the results are presented in <a class="figpopup" href="/books/NBK55069/table/ml162.t1/?report=objectonly" target="object" rid-figpopup="figml162t1" rid-ob="figobml162t1">Tables 1</a>–<a class="figpopup" href="/books/NBK55069/table/ml162.t4/?report=objectonly" target="object" rid-figpopup="figml162t4" rid-ob="figobml162t4">4</a>.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml162t3"><a href="/books/NBK55069/table/ml162.t3/?report=objectonly" target="object" title="Table 3" class="img_link icnblk_img figpopup" rid-figpopup="figml162t3" rid-ob="figobml162t3"><img class="small-thumb" src="/books/NBK55069/table/ml162.t3/?report=thumb" src-large="/books/NBK55069/table/ml162.t3/?report=previmg" alt="Table 3. Summary of SAR on the Thiophene Portion." /></a><div class="icnblk_cntnt"><h4 id="ml162.t3"><a href="/books/NBK55069/table/ml162.t3/?report=objectonly" target="object" rid-ob="figobml162t3">Table 3</a></h4><p class="float-caption no_bottom_margin">Summary of SAR on the Thiophene Portion. </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml162t4"><a href="/books/NBK55069/table/ml162.t4/?report=objectonly" target="object" title="Table 4" class="img_link icnblk_img figpopup" rid-figpopup="figml162t4" rid-ob="figobml162t4"><img class="small-thumb" src="/books/NBK55069/table/ml162.t4/?report=thumb" src-large="/books/NBK55069/table/ml162.t4/?report=previmg" alt="Table 4. Summary of SAR on the Phenethylamine Portion." /></a><div class="icnblk_cntnt"><h4 id="ml162.t4"><a href="/books/NBK55069/table/ml162.t4/?report=objectonly" target="object" rid-ob="figobml162t4">Table 4</a></h4><p class="float-caption no_bottom_margin">Summary of SAR on the Phenethylamine Portion. </p></div></div><p>We first wanted to understand if the alpha-chloroamide moiety was essential for activity. Thus, we synthesized analogs where the chloro functional group has been replaced with a methyl, a methoxy, and a hydroxy group (entries 2–4, <a class="figpopup" href="/books/NBK55069/table/ml162.t1/?report=objectonly" target="object" rid-figpopup="figml162t1" rid-ob="figobml162t1">Table 1</a>). None of these analogs were found to be active, confirming that the alpha-chloroamide moiety is required for activity.</p><p>Considering that the probe is acting as a somewhat selective alkylating agent, replacing the chloro functional group with a heterocyclic leaving group could lead to an improved selectivity for the HRAS<sup>V12</sup> cell lines. We, thus, synthesized the 2-thiopyrimydyl analog of the probe (entry 5, <a class="figpopup" href="/books/NBK55069/table/ml162.t1/?report=objectonly" target="object" rid-figpopup="figml162t1" rid-ob="figobml162t1">Table 1</a>). However, it was found to be inactive as well, further confirming that the α-chloroamide moiety is necessary for activity.</p><p>Next, we investigated the influence of the substitution on the aniline aromatic ring (<a class="figpopup" href="/books/NBK55069/table/ml162.t2/?report=objectonly" target="object" rid-figpopup="figml162t2" rid-ob="figobml162t2">Table 2</a>). Both the meta-chloro substitutent and the para-methoxy substitutent were found to be critical for activity, as removal of either one led to a 10-fold decrease in activity (entries 2 and 4<b>, </b><a class="figpopup" href="/books/NBK55069/table/ml162.t2/?report=objectonly" target="object" rid-figpopup="figml162t2" rid-ob="figobml162t2">Table 2</a>).</p><p>The presence of a thiophene ring could be a potential liability for the probe. Thiophene can easily be oxidized <i>in vivo</i> and undergo Michael addition. Thus, we used different aldehyde components in the Ugi reaction to try to replace the thiophene moiety of the probe (<a class="figpopup" href="/books/NBK55069/table/ml162.t3/?report=objectonly" target="object" rid-figpopup="figml162t3" rid-ob="figobml162t3">Table 3</a>). Replacing the thiophene ring with hydrophobic group such as a cyclohexyl or an isopropyl group (entries 1 and 2, <a class="figpopup" href="/books/NBK55069/table/ml162.t3/?report=objectonly" target="object" rid-figpopup="figml162t3" rid-ob="figobml162t3">Table 3</a>) led to a decrease in activity and selectivity. We, thus, tried to replace the thiophene ring with a thiazole (entry 3, <a class="figpopup" href="/books/NBK55069/table/ml162.t3/?report=objectonly" target="object" rid-figpopup="figml162t3" rid-ob="figobml162t3">Table 3</a>) or a 2-chlorothiophene (entry 4, <a class="figpopup" href="/books/NBK55069/table/ml162.t3/?report=objectonly" target="object" rid-figpopup="figml162t3" rid-ob="figobml162t3">Table 3</a>) in order to deactivate the 3-position toward Michael addition. The thiazole analog was found to be almost inactive with an IC<sub>50</sub> of only 8.26 μM but the 2-chlorothiophene analog was found to be very potent with an IC<sub>50</sub> of 61 nM in BJeLR cell line. However, its selectivity was only of 2.2-fold. We also tried to completely remove the thiophene ring in order to address the presence of a stereogenic center in the molecule. We used formaldehyde or acetone in the Ugi reaction in order to get a simple methylene group (entry 5, <a class="figpopup" href="/books/NBK55069/table/ml162.t3/?report=objectonly" target="object" rid-figpopup="figml162t3" rid-ob="figobml162t3">Table 3</a>) or a gem-dimethyl group (entry 6, <a class="figpopup" href="/books/NBK55069/table/ml162.t3/?report=objectonly" target="object" rid-figpopup="figml162t3" rid-ob="figobml162t3">Table 3</a>), respectively, in place of the thiophene ring. The gem-dimethyl analog was particularly potent with an IC<sub>50</sub> of 58 nM in BJeLR cell line but lacked the selectivity.</p><p>IA=Inactive; m=mouse; ND=Not determined; PPB(h)=Plasma protein binding in human; PS(h)=Plasma stability in humanWe finally studied the influence of the phenethylamine portion of the probe by using different isocyanide components in the Ugi reaction (<a class="figpopup" href="/books/NBK55069/table/ml162.t4/?report=objectonly" target="object" rid-figpopup="figml162t4" rid-ob="figobml162t4">Table 4</a>). Shorter hydrophobic amines (entries 1 and 2, <a class="figpopup" href="/books/NBK55069/table/ml162.t4/?report=objectonly" target="object" rid-figpopup="figml162t4" rid-ob="figobml162t4">Table 4</a>) were tolerated for activity but not for selectivity. Introduction of a sulfone group (entry 3, <a class="figpopup" href="/books/NBK55069/table/ml162.t4/?report=objectonly" target="object" rid-figpopup="figml162t4" rid-ob="figobml162t4">Table 4</a>) led to a slight improvement in solubility and comparable activity to the probe, but at the cost of selectivity, which was only of 2.3. Using a benzotriazole ring (entry 4, <a class="figpopup" href="/books/NBK55069/table/ml162.t4/?report=objectonly" target="object" rid-figpopup="figml162t4" rid-ob="figobml162t4">Table 4</a>) also led to a very active compound but a weak selectivity.</p><p>While the presence of a potentially reactive alkylating group may be of concern in a drug development program, for purposes of a probe molecule, the more important consideration is selectivity against well designed counterscreens. As is apparent from the differential activity against HRAS<sup>V12</sup>- and non-HRAS<sup>V12</sup>-expressing cell lines, the biological effects of the functional group can be quite varied in different contexts. This differential activity is also apparent from the range of activities seen by the multiple analogs that contain this group and were tested in the four cell lines. While there are many potent compounds, there are also over a dozen alpha-chloroamide-containing compounds that show no activity in any of the four lines, including compounds (such as 2345373; entry 8<b>, </b><a class="figpopup" href="/books/NBK55069/table/ml162.t5/?report=objectonly" target="object" rid-figpopup="figml162t5" rid-ob="figobml162t5">Table 5</a>) that are similar to the known active RSL3. These inactive compounds have displayed activity in other mammalian cell-based assays in Pubchem (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/598" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 598</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1381" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 1381</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1814" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 1814</a>). Therefore, these compounds are apparently cell permeable but inactive in the BJ-fibroblast derived cell lines. It is also unlikely that the alpha-chloroamide substituent in the compounds is reacting with any abundant nucleophile common to all cell lines, as they are inert in the presence of physiological levels of glutathione.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml162t5"><a href="/books/NBK55069/table/ml162.t5/?report=objectonly" target="object" title="Table 5" class="img_link icnblk_img figpopup" rid-figpopup="figml162t5" rid-ob="figobml162t5"><img class="small-thumb" src="/books/NBK55069/table/ml162.t5/?report=thumb" src-large="/books/NBK55069/table/ml162.t5/?report=previmg" alt="Table 5. Summary of SAR for Other Alpha-Chloroamide Analogs." /></a><div class="icnblk_cntnt"><h4 id="ml162.t5"><a href="/books/NBK55069/table/ml162.t5/?report=objectonly" target="object" rid-ob="figobml162t5">Table 5</a></h4><p class="float-caption no_bottom_margin">Summary of SAR for Other Alpha-Chloroamide Analogs. </p></div></div><p>Some researchers have also suggested that chemical probes that can covalently modify targets may have some benefits in biological discovery (<a class="bibr" href="#ml162.r25" rid="ml162.r25">25</a>, <a class="bibr" href="#ml162.r26" rid="ml162.r26">26</a>), and such probes have been reported (<a class="bibr" href="#ml162.r27" rid="ml162.r27">27</a>). In the case of a probe such as the one described herein that was identified through phenotypic screening and, therefore, does not have an identified molecular target, covalent modification may facilitate the target identification process. Furthermore, similar reactive groups can occasionally be found in marketed drugs, such as the chloromethyl ketone in the glucocorticoid mometasone. This finding suggests that with the proper modulation of activity these compounds can be selectively targeted. In the case of this project, the selectivity exhibited by the probe compound allows it to serve as a useful tool for investigating HRAS<sup>V12</sup> cancer cell biology.</p><p><a class="figpopup" href="/books/NBK55069/table/ml162.t5/?report=objectonly" target="object" rid-figpopup="figml162t5" rid-ob="figobml162t5">Table 5</a> shows alpha-chloroamide analogs that were also found as hit during the screening campaign (entries 1–7, <a class="figpopup" href="/books/NBK55069/table/ml162.t5/?report=objectonly" target="object" rid-figpopup="figml162t5" rid-ob="figobml162t5">Table 5</a>) and several inactive alpha-chloroamides (entries 8–10, <a class="figpopup" href="/books/NBK55069/table/ml162.t5/?report=objectonly" target="object" rid-figpopup="figml162t5" rid-ob="figobml162t5">Table 5</a>).</p></div><div id="ml162.s26"><h3>3.5. Cellular Activity</h3><p>All assays used in this project were cellular cytotoxicity assays, with the probe selected on the basis of selective cellular growth inhibition. Therefore, no additional testing of cell toxicity or cell permeability was necessary.</p></div><div id="ml162.s27"><h3>3.6. Profiling Assays</h3><p>A search of PubChem for the probe compound (CID 3689413) shows that the probe has been screened in 360 different assays and was identified as active in 11 other assays (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2675" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2675</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/435010" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 435010</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/485297" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 485297</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/449750" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 449750</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1045" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 1045</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/485313" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 485313</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/434968" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 434968</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1047" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 1047</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/449749" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 449749</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/449756" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 449756</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/463229" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 463229</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/485364" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 485364</a>). This relatively low hit rate is somewhat surprising based on the putative reactivity of the alpha-chloroamide; however, the selectivity observed in the screening assays, stability assays, and subsequent profiling experiments suggests that the reactivity is tempered and is dependent on the particular conditions to which the compound is exposed. In order to further validate this selective reactivity, we plan to perform further off-target testing through a standard commercial panel (CEREP/Ricerca).</p><p>The compound was also submitted for testing in the NCI60 cancer cell line panel and has been testing in over 20 additional cancer cell lines. Initial results confirm significant differences in potency across different cancer cell lines and lineages. These results further reinforce the hypothesis that while the alpha-chloroamide may be covalently reacting with a target, it is not generally reactive or toxic to all mammalian cells.</p></div></div><div id="ml162.s28"><h2 id="_ml162_s28_">4. Discussion</h2><p>A novel, selective, potent probe (CID 3689413/<a href="/pcsubstance/?term=ML162[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML162</a>) was identified by high throughput screening of the NIH molecular libraries screening collection. While the probe itself and many related compounds in the collection are superficially unattractive for probe development due to the presence of an apparently nonselective reactive group, the activity profile of probe CID 3689413/<a href="/pcsubstance/?term=ML162[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML162</a> suggests that, in fact, many of these unattractive molecules may be developed into useful biological research tools. Further SAR confirmed that the reactive group is the key substituent for activity but that a range of potency and selectivity can be engineered by adjusting other molecular functionality.</p><div id="ml162.s29"><h3>4.1. Comparison to Existing Art and How the New Probe is an Improvement</h3><p>Probe CID 3689413/<a href="/pcsubstance/?term=ML162[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML162</a> is an improvement over the existing art. The two compounds previously identified using the same screening method are: erastin and RSL3. Erastin effectively inhibits the engineered HRAS<sup>V12</sup>-expressing cell lines with a low micromolar IC<sub>50</sub> and 4-fold selectivity over isogenic non-HRAS<sup>V12</sup>-expressing cells. A molecular target, voltage-dependent anion channels (VDACs), has also been determined for erastin (<a class="bibr" href="#ml162.r19" rid="ml162.r19">19</a>). RSL3 is more potent (IC<sub>50</sub> approximately100 nM) and somewhat more selective, although the molecular target is not known. Chemically and phenotypically, probe CID 3689413/<a href="/pcsubstance/?term=ML162[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML162</a> appears more similar to RSL3 but is more potent and selective than the known molecule and may have a different mode of action. Further profiling activity in nonengineered cancer cells will demonstrate the importance of multiple probes with different activity patterns and may lead to identification of novel pathways important for small-molecule susceptibility of cancers.</p><p>Investigation into relevant prior art entailed searching the following databases: SciFinder, Reaxys, PubChem, PubMed, US Patent and Trademark Office (USPTO), PatFT, AppFT, and World Intellectual Property Organization (WIPO). The search terms applied and hit statistics are provided in <a class="figpopup" href="/books/NBK55069/table/ml162.t6/?report=objectonly" target="object" rid-figpopup="figml162t6" rid-ob="figobml162t6">Table 6</a>. Abstracts were obtained for all references returned and were analyzed for relevance to the current project. The searches were performed on and are current as of January 26, 2011.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml162t6"><a href="/books/NBK55069/table/ml162.t6/?report=objectonly" target="object" title="Table 6" class="img_link icnblk_img figpopup" rid-figpopup="figml162t6" rid-ob="figobml162t6"><img class="small-thumb" src="/books/NBK55069/table/ml162.t6/?report=thumb" src-large="/books/NBK55069/table/ml162.t6/?report=previmg" alt="Table 6. Search Strings and Databases Employed in the Prior Art Search." /></a><div class="icnblk_cntnt"><h4 id="ml162.t6"><a href="/books/NBK55069/table/ml162.t6/?report=objectonly" target="object" rid-ob="figobml162t6">Table 6</a></h4><p class="float-caption no_bottom_margin">Search Strings and Databases Employed in the Prior Art Search. </p></div></div><p>The literature and patent searches summarized in <a class="figpopup" href="/books/NBK55069/table/ml162.t6/?report=objectonly" target="object" rid-figpopup="figml162t6" rid-ob="figobml162t6">Table 6</a> uncovered three small molecules that are known to be selectively lethal to cell lines harboring an HRAS mutation (HRAS<sup>V12</sup>), namely erastin, RSL-3, and RSL-5, (see <a class="figpopup" href="/books/NBK55069/figure/ml162.f2/?report=objectonly" target="object" rid-figpopup="figml162f2" rid-ob="figobml162f2">Figure 2</a>).</p></div><div id="ml162.s30"><h3>4.2. Mechanism of Action Studies</h3><p>The putative mechanism of action, based on the design of the primary and counterscreens, involves a target related to expression of oncogenic HRAS. As is demonstrated by the prior art, this does not mean the target is HRAS or on the RAS pathway; rather, the direct molecular target may be involved in processes that are merely more sensitive to inhibition when oncogenic HRAS is expressed. In the case of erastin, such a target has been shown to be VDACs. For the current probe, the likely mechanism of covalent modification by the alpha-chloroamide may be exploited to identify the molecular target by proteomic analysis or by appending an affinity tag (e.g., biotin) to the probe to capture the modified target.</p><p>A genetic method to identify a target is the use of RNAi in conjunction with the probe compound. A reduction of the target of probe CID 3689413/<a href="/pcsubstance/?term=ML162[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML162</a> may result in a similar activity profile in various cancer cell lines and will synergize with lower doses of the probe. The Broad Institute has created an RNAi platform dedicated to genome-scale experiments for the systematic application of RNA knockdown methods. Both historical data mining and future experiments can be used to identify candidate genes and pathways that are responsible for the selective phenotype of this molecule.</p><p>We are also using profile experiments to determine additional correlations with sensitivity to the probe. Upon completion of NCI60 panel profiling, correlations will be attempted to the known genetic characteristics of these cell lines. We have also added this probe to a small set of approximately 300 compounds that are being profiled against a larger (1000) panel of cell lines as part of another initiative underway at the Broad Institute (<a class="bibr" href="#ml162.r28" rid="ml162.r28">28</a>). This profiling analysis will correlate effects of the probe on cell viability and other cellular markers with gene expression data. Additional hypotheses can then be generated as to the molecular pathway or target of probe CID 3689413/<a href="/pcsubstance/?term=ML162[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML162</a>.</p></div><div id="ml162.s31"><h3>4.3. Planned Future Studies</h3><p>Probe CID 3689413/<a href="/pcsubstance/?term=ML162[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML162</a> was identified through a series of phenotypic screens. Therefore, one of the key uses of this probe will be the identification of a molecular target or pathway, as described above, which confers selective toxicity in cancer cells with certain genetic expression profiles. This can be done through biochemical and proteomic studies in an attempt to capture and identify the direct binding partner.</p><p>Another approach involves additional profiling in a sufficient number of well characterized cell lines to correlate sensitivity to the probe with genetic features. This is the goal of the 1000-cell line profiling already underway using probe CID 3689413/<a href="/pcsubstance/?term=ML162[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML162</a>.</p><p>As a designated probe compound, CID 3689413/<a href="/pcsubstance/?term=ML162[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML162</a> will, by default, be included in several planned studies at the Broad Institute that will characterize the MLSMR probe set. The Broad Institute Center Driven Research Project (CDRP) will profile probes, analogs, and a subset of less characterized compounds from the MLSMR using both multi-parametric image-based analysis and 1000-plex Luminex gene expression arrays in a well-defined cancer cell line, U2OS. In addition, probe compounds will be further characterized in 1000-plex gene expression arrays in up to 20 additional cell lines. These and other profiling approaches will continue to enhance the understanding of the mechanism of action and applicability of probes such as CID 3689413/<a href="/pcsubstance/?term=ML162[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML162</a>.</p><p>We envision that as this probe continues to be developed, it will become a common tool for testing susceptibility of cancers to specific inhibition and differentiating between genetic features. Additional characterization of probe CID 3689413/<a href="/pcsubstance/?term=ML162[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML162</a> through more widespread use will further define its phenotypic properties, continuing to enhance its utility as a research tool for cancer biology.</p></div></div><div id="ml162.reflist"><h2 id="_ml162_reflist_">5. 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Ras oncogenes in human cancer: a review. <span><span class="ref-journal">Cancer Res. </span>1989 Sep 1;<span class="ref-vol">49</span>(17):4682–4689.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/2547513" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 2547513</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>5.</dt><dd><div class="bk_ref" id="ml162.r5">Malumbre M, Barbacid M. Ras oncogenes: the first 30 years. <span><span class="ref-journal">Nat Rev Cancer. </span>2003 Jun;<span class="ref-vol">3</span>(6):459–465.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12778136" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12778136</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>6.</dt><dd><div class="bk_ref" id="ml162.r6">Downward J. Targeting RAS signalling pathways in cancer therapy. <span><span class="ref-journal">Nat Rev Cancer. </span>2003 Jan;<span class="ref-vol">3</span>(1):11–22.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12509763" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12509763</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>7.</dt><dd><div class="bk_ref" id="ml162.r7">Coleman ML, Marshall CJ, Olson MF. RAS and RHO GTPases in G1-phase cell-cycle regulation. <span><span class="ref-journal">Nat Rev Mol Cell Biol. </span>2004 May;<span class="ref-vol">5</span>(5):355–366.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15122349" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15122349</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>8.</dt><dd><div class="bk_ref" id="ml162.r8">Mizuarai S, Kotani H. Synthetic lethal interactions for the development of cancer therapeutics: biological and methodological advancements. <span><span class="ref-journal">Hum Genet. </span>2010 Dec;<span class="ref-vol">128</span>(6):567–575.</span> Epub 2010 Oct 26. [<a href="https://pubmed.ncbi.nlm.nih.gov/20976469" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20976469</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>9.</dt><dd><div class="bk_ref" id="ml162.r9">Luo J, Emanuele MJ, Li D, Creighton CJ, Schlabach MR, Westbrook TF, Wong KK, Elledge SJ. A genome-wide RNAi screen identifies multiple synthetic lethal interactions with the Ras oncogene. <span><span class="ref-journal">Cell. </span>2009 May 29;<span class="ref-vol">137</span>(5):835–848.</span> [<a href="/pmc/articles/PMC2768667/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2768667</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19490893" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19490893</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>10.</dt><dd><div class="bk_ref" id="ml162.r10">Puyol M, Martin A, Dubus P, Mulero F, Pizcueta P, Khan G, Guerra C, Santamaria D, Barbacid M. A synthetic lethal interaction between K-Ras oncogenes and Cdk4 unveils a therapeutic strategy for non-small cell lung carcinoma. <span><span class="ref-journal">Cancer Cell. </span>2010 Jul 13;<span class="ref-vol">18</span>:63–73.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/20609353" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20609353</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>11.</dt><dd><div class="bk_ref" id="ml162.r11">Scholl C, Frohling S, Dunn IF, Schinzel AC, Barbie DA, Kim SY, Silver SJ, Tamayo P, Wadlow RC, Ramaswamy S, et al. Synthetic lethal interaction between oncogenic KRAS dependency and STK33 suppression in human cancer cells. <span><span class="ref-journal">Cell. </span>2009 May 29;<span class="ref-vol">137</span>(5):821–834.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/19490892" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19490892</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>12.</dt><dd><div class="bk_ref" id="ml162.r12">Barbie DA, Tamayo P, Boehm JS, Kim SY, Moody SE, Dunn IF, Schinzel AC, Sandy P, Meylan E, Scholl C, et al. Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1. <span><span class="ref-journal">Nature. </span>2009 Nov 5;<span class="ref-vol">462</span>:108–114.</span> Epub 2009 Oct 21. [<a href="/pmc/articles/PMC2783335/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2783335</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19847166" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19847166</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>13.</dt><dd><div class="bk_ref" id="ml162.r13">Rudolph D, Steegmaier M, Hoffmann M, Grauert M, Baum A, Quant J, Haslinger C, Garin-Chesa P, Adolf GR. BI 6727, a Polo-like kinase inhibitor with improved pharmacokinetic profile and broad antitumor activity. <span><span class="ref-journal">Clin Cancer Res. </span>2009 May 1;<span class="ref-vol">15</span>(9):3094–3102.</span> Epub 2009 Apr 21. [<a href="https://pubmed.ncbi.nlm.nih.gov/19383823" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19383823</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>14.</dt><dd><div class="bk_ref" id="ml162.r14">Clark K, Plater L, Peggie M, Cohen P. Use of the pharmacological inhibitor BX795 to study the regulation and physiological roles of TBK1 and IkappaB kinase epsilon: a distinct upstream kinase mediates Ser-172 phosphorylation and activation. <span><span class="ref-journal">J Biol Chem. </span>2009 May 22;<span class="ref-vol">284</span>(21):14136–14146.</span> Epub 2009 Mar 22. [<a href="/pmc/articles/PMC2682862/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2682862</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19307177" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19307177</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>15.</dt><dd><div class="bk_ref" id="ml162.r15">Menu E, Garcia J, Huang X, Di Liberto M, Toogood PL, Chen I, Vanderkerken K, Chen-Kiang S. A novel therapeutic combination using PD 0332991 and bortezomib: study in the 5T33MM myeloma model. <span><span class="ref-journal">Cancer Res. </span>2008 Jul 15;<span class="ref-vol">68</span>(14):5519–5523.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18632601" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18632601</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>16.</dt><dd><div class="bk_ref" id="ml162.r16">Guo W, Wu S, Liu J, Fang B. Identification of a small molecule with synthetic lethality for K-Ras and protein kinase C Iota. <span><span class="ref-journal">Cancer Res. </span>2008 Sep 15;<span class="ref-vol">68</span>(18):7403–7408.</span> [<a href="/pmc/articles/PMC2678915/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2678915</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18794128" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18794128</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>17.</dt><dd><div class="bk_ref" id="ml162.r17">Dolma S, Lessnick SL, Hanh WC, Stockwell BR. Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells. <span><span class="ref-journal">Cancer Cell. </span>2003 Mar 3;(3):285–296.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12676586" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12676586</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>18.</dt><dd><div class="bk_ref" id="ml162.r18">Yang WS, Stockwell BR. Synthetic lethal screening identifies compounds activating iron-dependent, nonapoptotic cell death in oncogenic-RAS-harboring cancer cells. <span><span class="ref-journal">Chem Biol. </span>2008 Mar;<span class="ref-vol">15</span>(3):234–245.</span> [<a href="/pmc/articles/PMC2683762/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2683762</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18355723" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18355723</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>19.</dt><dd><div class="bk_ref" id="ml162.r19">Yagoda N, von Rechenberg M, Zganjor E, Bauer AJ, Yang WS, Fridman DJ, Wolpaw AJ, Smukste I, Peltier JM, Boniface JJ, et al. RAS–RAF–MEK-dependent oxidative cell death involving voltage-dependent anion channels. <span><span class="ref-journal">Nature. </span>2007 Jun 14;<span class="ref-vol">447</span>(7146):864–868.</span> [<a href="/pmc/articles/PMC3047570/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3047570</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/17568748" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17568748</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>20.</dt><dd><div class="bk_ref" id="ml162.r20">Hanh WC. Immortalization and transformation of human cells. <span><span class="ref-journal">Mol Cells. </span>2002 Jun 30;<span class="ref-vol">13</span>(3):351–361.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12132573" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12132573</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>21.</dt><dd><div class="bk_ref" id="ml162.r21">Hanh WC, Counter CM, Lundberg AS, Beijersbergen RL, Brooks MW, Weinberg RA. Creation of human tumour cells with defined genetic elements. <span><span class="ref-journal">Nature. </span>1999 Jul 29;<span class="ref-vol">400</span>(6743):464–468.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/10440377" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10440377</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>22.</dt><dd><div class="bk_ref" id="ml162.r22">Hanh WC, Dessain SK, Brooks MW, King JE, Elenbaas B, Sabatini DM, DeCaprio JA, Weinberg RA. Enumeration of the simian virus 40 early region elements necessary for human cell transformation. <span><span class="ref-journal">Mol Cell Biol. </span>2002 Apr;<span class="ref-vol">22</span>(7):2111–2123.</span> [<a href="/pmc/articles/PMC133688/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC133688</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/11884599" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11884599</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>23.</dt><dd><div class="bk_ref" id="ml162.r23">Hanh WC, Weinberg RA. Modelling the molecular circuitry of cancer. <span><span class="ref-journal">Nat Rev Cancer. </span>2002 May;<span class="ref-vol">2</span>(5):331–341.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12044009" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12044009</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>24.</dt><dd><div class="bk_ref" id="ml162.r24">Hanh WC, Weinberg RA. Rules for making human tumor cells. <span><span class="ref-journal">N Engl J Med. </span>2002 Nov 14;<span class="ref-vol">347</span>(20):1593–1603.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12432047" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12432047</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>25.</dt><dd><div class="bk_ref" id="ml162.r25">Cravatt BF, Wright AT, Kozarich JW. Activity-based protein profiling: from enzyme chemistry to proteomic chemistry. <span><span class="ref-journal">Annu Rev Biochem. </span>2008;<span class="ref-vol">77</span>:383–414.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18366325" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18366325</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>26.</dt><dd><div class="bk_ref" id="ml162.r26">Bachovchin DA, Brown SJ, Rosen H, Cravatt BF. Identification of selective inhibitors of uncharacterized enzymes by high-throughput screening with fluorescent activity-based probes. <span><span class="ref-journal">Nat Biotechnol. </span>2009 Apr;<span class="ref-vol">27</span>(4):387–394.</span> Epub 2009 Mar 29. [<a href="/pmc/articles/PMC2709489/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2709489</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19329999" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19329999</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>27.</dt><dd><div class="bk_ref" id="ml162.r27">Bachovchin DA, Wolfe MR, Masuda K, Brown SJ, Spicer TP, Fernandez-Vega V, Chase P, Hoder PS, Rosen H, Cravatt BF. Oxime esters as selective, covalent inhibitors of the serine hydrolase retinoblastoma-binding protein 9 (RBBP9). <span><span class="ref-journal">Bioorg Med Chem Lett. </span>2010 Apr 1;<span class="ref-vol">20</span>(7):2254–2258.</span> Epub 2010 Feb 6. [<a href="/pmc/articles/PMC2843764/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2843764</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20207142" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20207142</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>28.</dt><dd><div class="bk_ref" id="ml162.r28">Schreiber SL, Shamji AF, Clemons PA, Hon C, Koehler AN, Munoz B, Palmer M, Stern AM, Wagner BK, Powers S. for the Cancer Target, Discovery and Development Network. Towards patient-based cancer therapeutics. <span><span class="ref-journal">Nat Biotechnol. </span>2010 Sep;<span class="ref-vol">28</span>(9):904–906.</span> [Available on 2011/3/1] [<a href="/pmc/articles/PMC2939009/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2939009</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20829823" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20829823</span></a>]</div></dd></dl></dl></div><div id="ml162.appgroup1"><h2 id="_ml162_appgroup1_">6. Appendices</h2><div id="ml162.app1"><h3>Appendix A. Compound Characterization</h3><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml162t7"><a href="/books/NBK55069/table/ml162.t7/?report=objectonly" target="object" title="Table A1" class="img_link icnblk_img figpopup" rid-figpopup="figml162t7" rid-ob="figobml162t7"><img class="small-thumb" src="/books/NBK55069/table/ml162.t7/?report=thumb" src-large="/books/NBK55069/table/ml162.t7/?report=previmg" alt="Table A1. Summary of Completed Assays and AIDs." /></a><div class="icnblk_cntnt"><h4 id="ml162.t7"><a href="/books/NBK55069/table/ml162.t7/?report=objectonly" target="object" rid-ob="figobml162t7">Table A1</a></h4><p class="float-caption no_bottom_margin">Summary of Completed Assays and AIDs. </p></div></div></div><div id="ml162.app2"><h3>Appendix B. Detailed Assay Protocols</h3><div id="ml162.s36"><h4>Primary Screen for BJeLR Cell Viability</h4><ol><li class="half_rhythm"><div>Maintain cells in 35 mL of growth medium (per 1 Liter: 730 ml DMEM with 4 mM L-glutamine, 210 ml M199, 150 ml heat-inactivated fetal bovine serum (FBS) in a T175 cell culture flask.</div></li><li class="half_rhythm"><div>Incubate in a TC incubator at 95% humidity, 5% CO<sub>2</sub>, 37°C.</div></li><li class="half_rhythm"><div>To passage, harvest cells by first aspirating the media and rinsing the flask with 10 ml sterile PBS.</div></li><li class="half_rhythm"><div>Aspirate PBS and add 5 mL trypsin to the flask. Incubate for 5 minutes at 22°C.</div></li><li class="half_rhythm"><div>Add 8 mL of growth medium to the trypsin to quench the reaction.</div></li><li class="half_rhythm"><div>Resuspend the cells, count, and transfer 4.5 million cells in approximately 2 mL to 33 mL fresh growth medium in a new T175 flask. Carry the lines for no more than 20 passages.</div></li><li class="half_rhythm"><div>For screening, harvest the cells, and adjust the concentration to 33,000/mL. While gently stirring, disperse the cells with a Combi multidrop by adding 30 μL of suspension per well to white, sterile, TC-treated, 384-well plates for a total of 1000 cells per well. Incubate the plates overnight in an automated TC incubator at 95% humidity, 5% CO<sub>2</sub>, 37°C.</div></li><li class="half_rhythm"><div>For compound screening, add 50 nL or 100 nL of compound, depending on the desired final compound concentration, using slotted steel pins on a pin tool.</div></li><li class="half_rhythm"><div>Return the plates to the incubator for 48 hours. To read viability, remove the cells from the incubator and cool to room temperature for 30 minutes. Remove the lids, and add 30 μL of diluted CellTiter Glo (1:3 dilution with PBS) to each with a Combi Multidrop. Incubate the plates for 10 minutes, and detect luminescence on an Envision (Perkin-Elmer) multimode reader (0.1 seconds per well).</div></li></ol></div><div id="ml162.s37"><h4>Secondary Screen for BJeLR Cell Viability (Alamar Blue)</h4><ol><li class="half_rhythm"><div>Dilute the compounds into growth medium by adding 2 μL of DMSO compound solution to 148 μL of medium and mix thoroughly. Make dilutions in 384-well stock plates (Greiner, catalog no. 781270).</div></li><li class="half_rhythm"><div>Further dilute these plates in series by adding 75 μL of solution to 75 μL of fresh growth medium, proceeding across the 384-well plate, and generate concentration-response curves.</div></li><li class="half_rhythm"><div>Next, add 36 μL of cell suspension at 28,000 cells per well to the assay plates (1000 cells/well), and add 4 μL of the medium containing the dilution series of compound to the cells.</div></li><li class="half_rhythm"><div>Incubate the cells for 48 hours in a TC incubator at 95% humidity, 5% CO<sub>2</sub>, 37°C.</div></li><li class="half_rhythm"><div>To measure viability, add 10 μL Alamar Blue solution (50% in growth medium) to each well.</div></li><li class="half_rhythm"><div>Incubate the cells for 16 hours, and read fluorescence intensity (544 nM excitation, 590 nM emission.)</div></li></ol></div></div><div id="ml162.app3"><h3>Appendix C. NMR and LC Data of Probe and Analogs</h3><div id="ml162.fu2" class="figure bk_fig"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu27.jpg" alt="1H NMR Spectrum of the probe (CID 3689413/ML162)." /></div><h3><span class="title"><sup>1</sup>H NMR Spectrum of the probe (CID 3689413/<a href="/pcsubstance/?term=ML162[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML162</a>)</span></h3></div><div id="ml162.fu3" class="figure bk_fig"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu28.jpg" alt="13C NMR Spectrum of the Probe (CID 3689413/ML162)." /></div><h3><span class="title"><sup>13</sup>C NMR Spectrum of the Probe (CID 3689413/<a href="/pcsubstance/?term=ML162[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML162</a>)</span></h3></div><div id="ml162.fu4" class="figure bk_fig"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu29.jpg" alt="HPLC/MS Chromatogram of the Probe (CID 3689413/ML162) showing >95% purity." /></div><h3><span class="title">HPLC/MS Chromatogram of the Probe (CID 3689413/<a href="/pcsubstance/?term=ML162[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML162</a>) showing >95% purity</span></h3></div><div id="ml162.s42"><h4>Spectroscopic Data for SAR Analogs</h4><div id="ml162.fu5" class="figure bk_fig"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu30.jpg" alt="1HNMR Spectra (300 MHz, CDCl3) of Analog CID 46897912." /></div><h3><span class="title"><sup>1</sup>HNMR Spectra (300 MHz, CDCl<sub>3</sub>) of Analog CID 46897912</span></h3></div><div id="ml162.fu6" class="figure bk_fig"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu31.jpg" alt="UPLC Chromatogram of Analog CID 46897912." /></div><h3><span class="title">UPLC Chromatogram of Analog CID 46897912</span></h3></div><div id="ml162.fu7" class="figure bk_fig"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu32.jpg" alt="1HNMR Spectra (300 MHz, CDCl3) of Analog CID 46897909." /></div><h3><span class="title"><sup>1</sup>HNMR Spectra (300 MHz, CDCl<sub>3</sub>) of Analog CID 46897909</span></h3></div><div id="ml162.fu8" class="figure bk_fig"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu33.jpg" alt="UPLC Chromatogram of Analog CID 46897909." /></div><h3><span class="title">UPLC Chromatogram of Analog CID 46897909</span></h3></div><div id="ml162.fu9" class="figure bk_fig"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu34.jpg" alt="1HNMR Spectra (300 MHz, CDCl3) of Analog CID 46897907." /></div><h3><span class="title"><sup>1</sup>HNMR Spectra (300 MHz, CDCl<sub>3</sub>) of Analog CID 46897907</span></h3></div><div id="ml162.fu10" class="figure bk_fig"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu35.jpg" alt="UPLC Chromatogram of Analog CID 46897907." /></div><h3><span class="title">UPLC Chromatogram of Analog CID 46897907</span></h3></div><div id="ml162.fu11" class="figure bk_fig"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu36.jpg" alt="1HNMR Spectra (300 MHz, CDCl3) of Analog CID 49766533." /></div><h3><span class="title"><sup>1</sup>HNMR Spectra (300 MHz, CDCl<sub>3</sub>) of Analog CID 49766533</span></h3></div><div id="ml162.fu12" class="figure bk_fig"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu37.jpg" alt="UPLC Chromatogram of Analog CID 49766533." /></div><h3><span class="title">UPLC Chromatogram of Analog CID 49766533</span></h3></div><div id="ml162.fu13" class="figure bk_fig"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu38.jpg" alt="1HNMR Spectra (300 MHz, CDCl3) of Analog CID 3689416." /></div><h3><span class="title"><sup>1</sup>HNMR Spectra (300 MHz, CDCl<sub>3</sub>) of Analog CID 3689416</span></h3></div><div id="ml162.fu14" class="figure bk_fig"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu39.jpg" alt="UPLC Chromatogram of Analog CID 3689416." /></div><h3><span class="title">UPLC Chromatogram of Analog CID 3689416</span></h3></div><div id="ml162.fu15" class="figure bk_fig"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu40.jpg" alt="1HNMR Spectra (300 MHz, CDCl3) of Analog CID 3689415." /></div><h3><span class="title"><sup>1</sup>HNMR Spectra (300 MHz, CDCl<sub>3</sub>) of Analog CID 3689415</span></h3></div><div id="ml162.fu16" class="figure bk_fig"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu41.jpg" alt="UPLC Chromatogram of Analog CID 3689415." /></div><h3><span class="title">UPLC Chromatogram of Analog CID 3689415</span></h3></div><div id="ml162.fu17" class="figure bk_fig"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu42.jpg" alt="1HNMR Spectra (300 MHz, CDCl3) of Analog CID 3689414." /></div><h3><span class="title"><sup>1</sup>HNMR Spectra (300 MHz, CDCl<sub>3</sub>) of Analog CID 3689414</span></h3></div><div id="ml162.fu18" class="figure bk_fig"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu43.jpg" alt="UPLC Chromatogram of Analog CID 3689414." /></div><h3><span class="title">UPLC Chromatogram of Analog CID 3689414</span></h3></div><div id="ml162.fu19" class="figure bk_fig"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu44.jpg" alt="1HNMR (300 MHz, CDCl3) of Analog CID 46897904." /></div><h3><span class="title"><sup>1</sup>HNMR (300 MHz, CDCl<sub>3</sub>) of Analog CID 46897904</span></h3></div><div id="ml162.fu20" class="figure bk_fig"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu45.jpg" alt="UPLC Chromatogram of Analog CID 46897904." /></div><h3><span class="title">UPLC Chromatogram of Analog CID 46897904</span></h3></div><div id="ml162.fu21" class="figure bk_fig"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu46.jpg" alt="1HNMR Spectra (300 MHz, CDCl3) of Analog CID 49766510." /></div><h3><span class="title"><sup>1</sup>HNMR Spectra (300 MHz, CDCl<sub>3</sub>) of Analog CID 49766510</span></h3></div><div id="ml162.fu22" class="figure bk_fig"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu47.jpg" alt="UPLC Chromatogram of Analog CID 49766510." /></div><h3><span class="title">UPLC Chromatogram of Analog CID 49766510</span></h3></div><div id="ml162.fu23" class="figure bk_fig"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu48.jpg" alt="1HNMR Spectra (300 MHz, CDCl3) of Analog CID 49766537." /></div><h3><span class="title"><sup>1</sup>HNMR Spectra (300 MHz, CDCl<sub>3</sub>) of Analog CID 49766537</span></h3></div><div id="ml162.fu24" class="figure bk_fig"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu49.jpg" alt="UPLC Chromatogram of Analog CID 49766537." /></div><h3><span class="title">UPLC Chromatogram of Analog CID 49766537</span></h3></div><div id="ml162.fu25" class="figure bk_fig"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu50.jpg" alt="1HNMR Spectra (300 MHz, CDCl3) of Analog CID 49766511." /></div><h3><span class="title"><sup>1</sup>HNMR Spectra (300 MHz, CDCl<sub>3</sub>) of Analog CID 49766511</span></h3></div><div id="ml162.fu26" class="figure bk_fig"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu51.jpg" alt="UPLC Chromatogram of Analog CID 49766511." /></div><h3><span class="title">UPLC Chromatogram of Analog CID 49766511</span></h3></div><div id="ml162.fu27" class="figure bk_fig"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu52.jpg" alt="1HNMR Spectra (300 MHz, CDCl3) of Analog CID 49766514." /></div><h3><span class="title"><sup>1</sup>HNMR Spectra (300 MHz, CDCl<sub>3</sub>) of Analog CID 49766514</span></h3></div><div id="ml162.fu28" class="figure bk_fig"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu53.jpg" alt="UPLC Chromatogram of Analog CID 49766514." /></div><h3><span class="title">UPLC Chromatogram of Analog CID 49766514</span></h3></div><div id="ml162.fu29" class="figure bk_fig"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu54.jpg" alt="1HNMR Spectra (300 MHz, CDCl3) of Analog CID 49766515." /></div><h3><span class="title"><sup>1</sup>HNMR Spectra (300 MHz, CDCl<sub>3</sub>) of Analog CID 49766515</span></h3></div><div id="ml162.fu30" class="figure bk_fig"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu55.jpg" alt="UPLC Chromatogram of Analog CID 49766515." /></div><h3><span class="title">UPLC Chromatogram of Analog CID 49766515</span></h3></div><div id="ml162.fu31" class="figure bk_fig"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu56.jpg" alt="1HNMR Spectra (300 MHz, CDCl3) of Analog CID 5062094." /></div><h3><span class="title"><sup>1</sup>HNMR Spectra (300 MHz, CDCl<sub>3</sub>) of Analog CID 5062094</span></h3></div><div id="ml162.fu32" class="figure bk_fig"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu57.jpg" alt="UPLC Chromatogram of Analog CID 5062094." /></div><h3><span class="title">UPLC Chromatogram of Analog CID 5062094</span></h3></div><div id="ml162.fu33" class="figure bk_fig"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu58.jpg" alt="1HNMR Spectra (300 MHz, CDCl3) of Analog CID 49766544." /></div><h3><span class="title"><sup>1</sup>HNMR Spectra (300 MHz, CDCl<sub>3</sub>) of Analog CID 49766544</span></h3></div><div id="ml162.fu34" class="figure bk_fig"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu59.jpg" alt="UPLC Chromatogram of Analog CID 49766544." /></div><h3><span class="title">UPLC Chromatogram of Analog CID 49766544</span></h3></div><div id="ml162.fu35" class="figure bk_fig"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu60.jpg" alt="1HNMR Spectra (300 MHz, CDCl3) of Analog CID 49766532." /></div><h3><span class="title"><sup>1</sup>HNMR Spectra (300 MHz, CDCl<sub>3</sub>) of Analog CID 49766532</span></h3></div><div id="ml162.fu36" class="figure bk_fig"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu61.jpg" alt="UPLC Chromatogram of Analog CID 49766532." /></div><h3><span class="title">UPLC Chromatogram of Analog CID 49766532</span></h3></div><div id="ml162.fu37" class="figure bk_fig"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu62.jpg" alt="1HNMR Spectra (300 MHz, CDCl3) of Analog CID 49766508." /></div><h3><span class="title"><sup>1</sup>HNMR Spectra (300 MHz, CDCl<sub>3</sub>) of Analog CID 49766508</span></h3></div><div id="ml162.fu38" class="figure bk_fig"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu63.jpg" alt="UPLC Chromatogram of Analog CID 49766508." /></div><h3><span class="title">UPLC Chromatogram of Analog CID 49766508</span></h3></div><div id="ml162.fu39" class="figure bk_fig"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu64.jpg" alt="1HNMR Spectra (300 MHz, CDCl3) of Analog CID 46897910." /></div><h3><span class="title"><sup>1</sup>HNMR Spectra (300 MHz, CDCl<sub>3</sub>) of Analog CID 46897910</span></h3></div><div id="ml162.fu40" class="figure bk_fig"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu65.jpg" alt="UPLC Chromatogram of Analog CID 46897910." /></div><h3><span class="title">UPLC Chromatogram of Analog CID 46897910</span></h3></div><div id="ml162.fu41" class="figure bk_fig"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu66.jpg" alt="1HNMR Spectra (300 MHz, CDCl3) of Analog CID 4381125." /></div><h3><span class="title"><sup>1</sup>HNMR Spectra (300 MHz, CDCl<sub>3</sub>) of Analog CID 4381125</span></h3></div><div id="ml162.fu42" class="figure bk_fig"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu67.jpg" alt="UPLC Chromatogram of Analog CID 4381125." /></div><h3><span class="title">UPLC Chromatogram of Analog CID 4381125</span></h3></div><div id="ml162.fu43" class="figure bk_fig"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu68.jpg" alt="1HNMR (300 MHz, CDCl3) of Analog CID 2449454." /></div><h3><span class="title"><sup>1</sup>HNMR (300 MHz, CDCl<sub>3</sub>) of Analog CID 2449454</span></h3></div><div id="ml162.fu44" class="figure bk_fig"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu69.jpg" alt="UPLC Chromatogram of Analog CID 2449454." /></div><h3><span class="title">UPLC Chromatogram of Analog CID 2449454</span></h3></div><div id="ml162.fu45" class="figure bk_fig"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu70.jpg" alt="1HNMR Spectra (300 MHz, CDCl3) of Analog CID 2416356." /></div><h3><span class="title"><sup>1</sup>HNMR Spectra (300 MHz, CDCl<sub>3</sub>) of Analog CID 2416356</span></h3></div><div id="ml162.fu46" class="figure bk_fig"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu71.jpg" alt="UPLC Chromatogram of Analog CID 2416356." /></div><h3><span class="title">UPLC Chromatogram of Analog CID 2416356</span></h3></div><div id="ml162.fu47" class="figure bk_fig"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu72.jpg" alt="1HNMR Spectra (300 MHz, CDCl3) of Analog CID 6545175." /></div><h3><span class="title"><sup>1</sup>HNMR Spectra (300 MHz, CDCl<sub>3</sub>) of Analog CID 6545175</span></h3></div><div id="ml162.fu48" class="figure bk_fig"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu73.jpg" alt="UPLC Chromatogram of Analog CID 6545175." /></div><h3><span class="title">UPLC Chromatogram of Analog CID 6545175</span></h3></div><div id="ml162.fu49" class="figure bk_fig"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu74.jpg" alt="1HNMR Spectra (300 MHz, CDCl3) of Analog CID 1637653." /></div><h3><span class="title"><sup>1</sup>HNMR Spectra (300 MHz, CDCl<sub>3</sub>) of Analog CID 1637653</span></h3></div><div id="ml162.fu50" class="figure bk_fig"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu75.jpg" alt="UPLC Chromatogram of Analog CID 1637653." /></div><h3><span class="title">UPLC Chromatogram of Analog CID 1637653</span></h3></div><div id="ml162.fu51" class="figure bk_fig"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu76.jpg" alt="1HNMR Spectra (300 MHz, CDCl3) of Analog CID 2345373." /></div><h3><span class="title"><sup>1</sup>HNMR Spectra (300 MHz, CDCl<sub>3</sub>) of Analog CID 2345373</span></h3></div><div id="ml162.fu52" class="figure bk_fig"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu77.jpg" alt="UPLC Chromatogram of Analog CID 2345373." /></div><h3><span class="title">UPLC Chromatogram of Analog CID 2345373</span></h3></div><div id="ml162.fu53" class="figure bk_fig"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu78.jpg" alt="1HNMR Spectra (300 MHz, CDCl3) of Analog CID 566661." /></div><h3><span class="title"><sup>1</sup>HNMR Spectra (300 MHz, CDCl<sub>3</sub>) of Analog CID 566661</span></h3></div><div id="ml162.fu54" class="figure bk_fig"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu79.jpg" alt="UPLC Chromatogram of Analog CID 566661." /></div><h3><span class="title">UPLC Chromatogram of Analog CID 566661</span></h3></div><div id="ml162.fu55" class="figure bk_fig"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu80.jpg" alt="1HNMR Spectra (300 MHz, CDCl3) of Analog CID 2120347." /></div><h3><span class="title"><sup>1</sup>HNMR Spectra (300 MHz, CDCl<sub>3</sub>) of Analog CID 2120347</span></h3></div><div id="ml162.fu56" class="figure bk_fig"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu81.jpg" alt="UPLC Chromatogram of Analog CID 2120347." /></div><h3><span class="title">UPLC Chromatogram of Analog CID 2120347</span></h3></div></div></div><div id="ml162.app4"><h3>Appendix D. Compounds Submitted to BioFocus</h3><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml162t8"><a href="/books/NBK55069/table/ml162.t8/?report=objectonly" target="object" title="Table A2" class="img_link icnblk_img figpopup" rid-figpopup="figml162t8" rid-ob="figobml162t8"><img class="small-thumb" src="/books/NBK55069/table/ml162.t8/?report=thumb" src-large="/books/NBK55069/table/ml162.t8/?report=previmg" alt="Table A2. Probe and Analog Information." /></a><div class="icnblk_cntnt"><h4 id="ml162.t8"><a href="/books/NBK55069/table/ml162.t8/?report=objectonly" target="object" rid-ob="figobml162t8">Table A2</a></h4><p class="float-caption no_bottom_margin">Probe and Analog Information. </p></div></div></div></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK55069_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><p class="contrib-group"><h4>Authors</h4><span itemprop="author">Joshua A Bittker</span>,<sup>1</sup> <span itemprop="author">Michel Weiwer</span>,<sup>1</sup> <span itemprop="author">Kenichi Shimada</span>,<sup>2</sup> <span itemprop="author">Wan S Yang</span>,<sup>2</sup> <span itemprop="author">Lawrence MacPherson</span>,<sup>1</sup> <span itemprop="author">Sivaraman Dandapani</span>,<sup>1</sup> <span itemprop="author">Ben Munoz</span>,<sup>1</sup> <span itemprop="author">Michelle Palmer</span>,<sup>1</sup> <span itemprop="author">Brent R Stockwell</span>,<sup>2</sup> and <span itemprop="author">Stuart L Schreiber</span><sup>1,3</sup>.</p><h4>Affiliations</h4><div class="affiliation"><sup>1</sup>
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The Broad Institute Probe Development Center, Cambridge, MA</div><div class="affiliation"><sup>2</sup>
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Howard Hughes Medical Institute, Department of Biological Sciences and Department of Chemistry, Columbia University, New York, NY</div><div class="affiliation"><sup>3</sup>
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Howard Hughes Medical Institute, Chemistry & Chemical Biology, Harvard University, Cambridge, MA</div><h3>Publication History</h3><p class="small">Received: <span itemprop="datePublished">March 26, 2010</span>; Last Update: <span itemprop="dateModified">February 10, 2011</span>.</p><h3>Copyright</h3><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright Notice</a></div></div><h3>Publisher</h3><p>National Center for Biotechnology Information (US), Bethesda (MD)</p><h3>NLM Citation</h3><p>Bittker JA, Weiwer M, Shimada K, et al. Screen for RAS-Selective Lethal Compounds and VDAC Ligands - Probe 1. 2010 Mar 26 [Updated 2011 Feb 10]. In: Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010-. <span class="bk_cite_avail"></span></p></div><div class="small-screen-prev"><a href="/books/n/mlprobe/ml163/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M75,30 c-80,60 -80,0 0,60 c-30,-60 -30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Prev</text></svg></a></div><div class="small-screen-next"><a href="/books/n/mlprobe/ml161/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M25,30c80,60 80,0 0,60 c30,-60 30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Next</text></svg></a></div></article><article data-type="fig" id="figobml162fu1"><div id="ml162.fu1" class="figure"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162fu1.jpg" alt="Image ml162fu1" /></div></div></article><article data-type="table-wrap" id="figobml162tu1"><div id="ml162.tu1" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK55069/table/ml162.tu1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml162.tu1_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">IUPAC Chemical Name</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">(2-(3-chloro-N-(2-chloroacetyl)-4-methoxyanilino)-N-phenethyl-2-thiophen-2-ylacetamide</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">PubChem CID</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3689413</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Molecular Weight</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">477.40338 g/mol</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Molecular Formula</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">C<sub>23</sub>H<sub>22</sub>Cl<sub>2</sub>N<sub>2</sub>O<sub>3</sub>S</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">XlogP</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">5.2</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H-Bond Donor</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H-Bond Acceptor</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Rotatable Bond Count</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">9</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Exact Mass</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">476.072819</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Topological Polar Surface Area</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">86.9</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobml162tu2"><div id="ml162.tu2" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK55069/table/ml162.tu2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml162.tu2_lrgtbl__"><table><thead><tr><th id="hd_h_ml162.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CID/ML#</th><th id="hd_h_ml162.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Target Name</th><th id="hd_h_ml162.tu2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">IC<sub>50</sub>/EC<sub>50</sub> (nM) [SID, AID]</th><th id="hd_h_ml162.tu2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Anti-target Name(s)</th><th id="hd_h_ml162.tu2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">IC<sub>50</sub>/EC<sub>50</sub> (nM) [SID, AID]</th><th id="hd_h_ml162.tu2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Fold Selective</th><th id="hd_h_ml162.tu2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Secondary Assay(s) Name: IC<sub>50</sub>/EC<sub>50</sub> (nM) [SID, AID]</th></tr></thead><tbody><tr><td headers="hd_h_ml162.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CID 3689413/<a href="/pcsubstance/?term=ML162[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML162</a></td><td headers="hd_h_ml162.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">BJeLR (HRAS<sup>V12</sup>)</td><td headers="hd_h_ml162.tu2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">25 [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/87692475" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 87692475</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2608" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2608</a>]</td><td headers="hd_h_ml162.tu2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">BJeH-LT (w/o HRAS<sup>V12</sup>)</td><td headers="hd_h_ml162.tu2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">578 [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/87692475" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 87692475</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2609" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2609</a>]</td><td headers="hd_h_ml162.tu2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">23</td><td headers="hd_h_ml162.tu2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">DRD HRAS<sup>V12</sup>: 34 [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/87692475" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 87692475</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2607" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2607</a>];<br />BJeH (w/o HRAS<sup>V12</sup>): 2400 [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/87692475" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 87692475</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2611" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2611</a>]</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobml162t2"><div id="ml162.t2" class="table"><h3><span class="label">Table 2</span><span class="title">Summary of SAR on the Aniline Aromatic Ring</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK55069/table/ml162.t2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml162.t2_lrgtbl__"><table class="no_margin"><thead><tr><th id="hd_h_ml162.t2_1_1_1_1" colspan="4" rowspan="1" style="text-align:center;vertical-align:middle;">SAR Analysis on the Aniline Aromatic Ring</th><th id="hd_h_ml162.t2_1_1_1_2" colspan="3" rowspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu2.jpg" alt="Image ml162fu2.jpg" /></div></th><th id="hd_h_ml162.t2_1_1_1_3" colspan="4" rowspan="1" style="text-align:center;vertical-align:middle;">Potency (μM) mean ± S.E.M. (n=replicates)</th><th id="hd_h_ml162.t2_1_1_1_4" rowspan="3" colspan="1" headers="hd_h_ml162.t2_1_1_1_4" style="text-align:center;vertical-align:middle;">Target to Antitarget Fold selectivity</th></tr><tr><th headers="hd_h_ml162.t2_1_1_1_1 hd_h_ml162.t2_1_1_2_1" id="hd_h_ml162.t2_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">No.</th><th headers="hd_h_ml162.t2_1_1_1_1 hd_h_ml162.t2_1_1_2_2" id="hd_h_ml162.t2_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CID</th><th headers="hd_h_ml162.t2_1_1_1_1 hd_h_ml162.t2_1_1_2_3" id="hd_h_ml162.t2_1_1_2_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">SID</th><th headers="hd_h_ml162.t2_1_1_1_1 hd_h_ml162.t2_1_1_2_4" id="hd_h_ml162.t2_1_1_2_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">Broad ID</th><th headers="hd_h_ml162.t2_1_1_1_2 hd_h_ml162.t2_1_1_2_5" id="hd_h_ml162.t2_1_1_2_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"><sup>*</sup></th><th headers="hd_h_ml162.t2_1_1_1_2 hd_h_ml162.t2_1_1_2_6" id="hd_h_ml162.t2_1_1_2_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">R<sub>1</sub></th><th headers="hd_h_ml162.t2_1_1_1_2 hd_h_ml162.t2_1_1_2_7" id="hd_h_ml162.t2_1_1_2_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">R<sub>2</sub></th><th headers="hd_h_ml162.t2_1_1_1_3" id="hd_h_ml162.t2_1_1_2_8" colspan="2" rowspan="1" style="text-align:center;vertical-align:middle;">BJeLR</th><th headers="hd_h_ml162.t2_1_1_1_3" id="hd_h_ml162.t2_1_1_2_9" colspan="2" rowspan="1" style="text-align:center;vertical-align:middle;">BJeH-LT</th></tr><tr><th headers="hd_h_ml162.t2_1_1_1_3 hd_h_ml162.t2_1_1_2_8" id="hd_h_ml162.t2_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">n</th><th headers="hd_h_ml162.t2_1_1_1_3 hd_h_ml162.t2_1_1_2_8" id="hd_h_ml162.t2_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IC<sub>50</sub></th><th headers="hd_h_ml162.t2_1_1_1_3 hd_h_ml162.t2_1_1_2_9" id="hd_h_ml162.t2_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">n</th><th headers="hd_h_ml162.t2_1_1_1_3 hd_h_ml162.t2_1_1_2_9" id="hd_h_ml162.t2_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IC<sub>50</sub></th></tr></thead><tbody><tr><td headers="hd_h_ml162.t2_1_1_1_1 hd_h_ml162.t2_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml162.t2_1_1_1_1 hd_h_ml162.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3689413</td><td headers="hd_h_ml162.t2_1_1_1_1 hd_h_ml162.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">99495782</td><td headers="hd_h_ml162.t2_1_1_1_1 hd_h_ml162.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-A36275421</td><td headers="hd_h_ml162.t2_1_1_1_2 hd_h_ml162.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml162.t2_1_1_1_2 hd_h_ml162.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Cl</td><td headers="hd_h_ml162.t2_1_1_1_2 hd_h_ml162.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">OMe</td><td headers="hd_h_ml162.t2_1_1_1_3 hd_h_ml162.t2_1_1_2_8 hd_h_ml162.t2_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml162.t2_1_1_1_3 hd_h_ml162.t2_1_1_2_8 hd_h_ml162.t2_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.025 ± 0.001</td><td headers="hd_h_ml162.t2_1_1_1_3 hd_h_ml162.t2_1_1_2_9 hd_h_ml162.t2_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml162.t2_1_1_1_3 hd_h_ml162.t2_1_1_2_9 hd_h_ml162.t2_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.578 ± 0.412</td><td headers="hd_h_ml162.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">23</td></tr><tr><td headers="hd_h_ml162.t2_1_1_1_1 hd_h_ml162.t2_1_1_2_2 hd_h_ml162.t2_1_1_2_3 hd_h_ml162.t2_1_1_2_4 hd_h_ml162.t2_1_1_1_2 hd_h_ml162.t2_1_1_2_5 hd_h_ml162.t2_1_1_2_6 hd_h_ml162.t2_1_1_2_7 hd_h_ml162.t2_1_1_1_3 hd_h_ml162.t2_1_1_2_8 hd_h_ml162.t2_1_1_3_1 hd_h_ml162.t2_1_1_3_2 hd_h_ml162.t2_1_1_2_9 hd_h_ml162.t2_1_1_3_3 hd_h_ml162.t2_1_1_3_4 hd_h_ml162.t2_1_1_1_4" colspan="11" rowspan="1" style="text-align:center;vertical-align:middle;">Solubility (PBS): <0.5 μM; PPB(h): 98.9%, (m): 99.1%; PS(h): 48.2%, (m) 9.4%; Purity: 95%</td></tr><tr><td headers="hd_h_ml162.t2_1_1_1_1 hd_h_ml162.t2_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml162.t2_1_1_1_1 hd_h_ml162.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3689416</td><td headers="hd_h_ml162.t2_1_1_1_1 hd_h_ml162.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">99495784</td><td headers="hd_h_ml162.t2_1_1_1_1 hd_h_ml162.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-A72180425</td><td headers="hd_h_ml162.t2_1_1_1_2 hd_h_ml162.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml162.t2_1_1_1_2 hd_h_ml162.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">H</td><td headers="hd_h_ml162.t2_1_1_1_2 hd_h_ml162.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">OMe</td><td headers="hd_h_ml162.t2_1_1_1_3 hd_h_ml162.t2_1_1_2_8 hd_h_ml162.t2_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml162.t2_1_1_1_3 hd_h_ml162.t2_1_1_2_8 hd_h_ml162.t2_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.220</td><td headers="hd_h_ml162.t2_1_1_1_3 hd_h_ml162.t2_1_1_2_9 hd_h_ml162.t2_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml162.t2_1_1_1_3 hd_h_ml162.t2_1_1_2_9 hd_h_ml162.t2_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1.7</td><td headers="hd_h_ml162.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">7.8</td></tr><tr><td headers="hd_h_ml162.t2_1_1_1_1 hd_h_ml162.t2_1_1_2_2 hd_h_ml162.t2_1_1_2_3 hd_h_ml162.t2_1_1_2_4 hd_h_ml162.t2_1_1_1_2 hd_h_ml162.t2_1_1_2_5 hd_h_ml162.t2_1_1_2_6 hd_h_ml162.t2_1_1_2_7 hd_h_ml162.t2_1_1_1_3 hd_h_ml162.t2_1_1_2_8 hd_h_ml162.t2_1_1_3_1 hd_h_ml162.t2_1_1_3_2 hd_h_ml162.t2_1_1_2_9 hd_h_ml162.t2_1_1_3_3 hd_h_ml162.t2_1_1_3_4 hd_h_ml162.t2_1_1_1_4" colspan="11" rowspan="1" style="text-align:center;vertical-align:middle;">Solubility (PBS): ND; PPB(h): ND, (m): ND; PS(h): ND, (m) ND; Purity: 100%</td></tr><tr><td headers="hd_h_ml162.t2_1_1_1_1 hd_h_ml162.t2_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml162.t2_1_1_1_1 hd_h_ml162.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3689415</td><td headers="hd_h_ml162.t2_1_1_1_1 hd_h_ml162.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">99495783</td><td headers="hd_h_ml162.t2_1_1_1_1 hd_h_ml162.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-A39093044</td><td headers="hd_h_ml162.t2_1_1_1_2 hd_h_ml162.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml162.t2_1_1_1_2 hd_h_ml162.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">OMe</td><td headers="hd_h_ml162.t2_1_1_1_2 hd_h_ml162.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">H</td><td headers="hd_h_ml162.t2_1_1_1_3 hd_h_ml162.t2_1_1_2_8 hd_h_ml162.t2_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml162.t2_1_1_1_3 hd_h_ml162.t2_1_1_2_8 hd_h_ml162.t2_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.170</td><td headers="hd_h_ml162.t2_1_1_1_3 hd_h_ml162.t2_1_1_2_9 hd_h_ml162.t2_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml162.t2_1_1_1_3 hd_h_ml162.t2_1_1_2_9 hd_h_ml162.t2_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2.4</td><td headers="hd_h_ml162.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">14</td></tr><tr><td headers="hd_h_ml162.t2_1_1_1_1 hd_h_ml162.t2_1_1_2_2 hd_h_ml162.t2_1_1_2_3 hd_h_ml162.t2_1_1_2_4 hd_h_ml162.t2_1_1_1_2 hd_h_ml162.t2_1_1_2_5 hd_h_ml162.t2_1_1_2_6 hd_h_ml162.t2_1_1_2_7 hd_h_ml162.t2_1_1_1_3 hd_h_ml162.t2_1_1_2_8 hd_h_ml162.t2_1_1_3_1 hd_h_ml162.t2_1_1_3_2 hd_h_ml162.t2_1_1_2_9 hd_h_ml162.t2_1_1_3_3 hd_h_ml162.t2_1_1_3_4 hd_h_ml162.t2_1_1_1_4" colspan="11" rowspan="1" style="text-align:center;vertical-align:middle;">Solubility (PBS): ND; PPB(h): ND, (m): ND; PS(h): ND, (m) ND; Purity: 100%</td></tr><tr><td headers="hd_h_ml162.t2_1_1_1_1 hd_h_ml162.t2_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml162.t2_1_1_1_1 hd_h_ml162.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3689414</td><td headers="hd_h_ml162.t2_1_1_1_1 hd_h_ml162.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">103023290</td><td headers="hd_h_ml162.t2_1_1_1_1 hd_h_ml162.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-A15132775</td><td headers="hd_h_ml162.t2_1_1_1_2 hd_h_ml162.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml162.t2_1_1_1_2 hd_h_ml162.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Cl</td><td headers="hd_h_ml162.t2_1_1_1_2 hd_h_ml162.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">H</td><td headers="hd_h_ml162.t2_1_1_1_3 hd_h_ml162.t2_1_1_2_8 hd_h_ml162.t2_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml162.t2_1_1_1_3 hd_h_ml162.t2_1_1_2_8 hd_h_ml162.t2_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.156</td><td headers="hd_h_ml162.t2_1_1_1_3 hd_h_ml162.t2_1_1_2_9 hd_h_ml162.t2_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml162.t2_1_1_1_3 hd_h_ml162.t2_1_1_2_9 hd_h_ml162.t2_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.331</td><td headers="hd_h_ml162.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2.1</td></tr><tr><td headers="hd_h_ml162.t2_1_1_1_1 hd_h_ml162.t2_1_1_2_2 hd_h_ml162.t2_1_1_2_3 hd_h_ml162.t2_1_1_2_4 hd_h_ml162.t2_1_1_1_2 hd_h_ml162.t2_1_1_2_5 hd_h_ml162.t2_1_1_2_6 hd_h_ml162.t2_1_1_2_7 hd_h_ml162.t2_1_1_1_3 hd_h_ml162.t2_1_1_2_8 hd_h_ml162.t2_1_1_3_1 hd_h_ml162.t2_1_1_3_2 hd_h_ml162.t2_1_1_2_9 hd_h_ml162.t2_1_1_3_3 hd_h_ml162.t2_1_1_3_4 hd_h_ml162.t2_1_1_1_4" colspan="11" rowspan="1" style="text-align:center;vertical-align:middle;">Solubility (PBS): <0.5 μM; PPB(h): 90.8%, (m): 94.4%; PS(h): 3.3%, (m) 9.2%; Purity: 93%</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>*</dt><dd><div id="ml162.tfn1"><p class="no_margin">P=Purchased; S=Synthesized</p></div></dd></dl><dl class="bkr_refwrap"><dt></dt><dd><div id="ml162.tfn2"><p class="no_margin">IA=Inactive; m=mouse; ND=Not determined; PPB (h)=Plasma protein binding in human; PS(h)=Plasma stability in human</p></div></dd></dl></dl></div></div></div></article><article data-type="fig" id="figobml162f1"><div id="ml162.f1" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162f1.jpg" alt="Figure 1. RAS Synthetic Lethal Compounds Discovered Through RNAi Screens." /></div><h3><span class="label">Figure 1</span><span class="title">RAS Synthetic Lethal Compounds Discovered Through RNAi Screens</span></h3><div class="caption"><p>BI 6727, a PLK1 inhibitor (Boehringer Ingelheim)(<i>a</i>); BX 795, a TBK1 inhibitor (Berlex Biosciences) (<i>b</i>); PD 0332991, a CDK4 inhibitor (Pfizer) (<i>c</i>).</p></div></div></article><article data-type="fig" id="figobml162f2"><div id="ml162.f2" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162f2.jpg" alt="Figure 2. RAS Synthetic Lethal Compounds Discovered Through Phenotypic Screens." /></div><h3><span class="label">Figure 2</span><span class="title">RAS Synthetic Lethal Compounds Discovered Through Phenotypic Screens</span></h3><div class="caption"><p>Compound identified by Guo and colleagues that is synthetically lethal to K-RAS mutant cell lines (<i>a</i>); Compound previously identified by the Stockwell and colleagues that is synthetically lethal to H-RAS and K-RAS mutant cell lines.</p></div></div></article><article data-type="fig" id="figobml162f3"><div id="ml162.f3" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162f3.jpg" alt="Figure 3. Growth Inhibition of HRASV12 Expressing and Non-expressing Cell Lines by the Positive Control Compound Erastin (CID 11214940) Identified in Pilot Screening." /></div><h3><span class="label">Figure 3</span><span class="title">Growth Inhibition of HRAS<sup>V12</sup> Expressing and Non-expressing Cell Lines by the Positive Control Compound Erastin (CID 11214940) Identified in Pilot Screening</span></h3><div class="caption"><p>Growth inhibition concentration-response curves of erastin in engineered BJ fibroblasts expressing oncogenic HRas<sup>V12</sup> (BJeLR, DRD) or lacking HRas<sup>V12</sup> (BJeHLT, BJeH).</p></div></div></article><article data-type="fig" id="figobml162f4"><div id="ml162.f4" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162f4.jpg" alt="Figure 4. Growth Inhibition of HRASV12 Expressing and Non-expressing Cell Lines by the Positive Control Compound RSL3 (CID 40911229) Identified in Pilot Screening." /></div><h3><span class="label">Figure 4</span><span class="title">Growth Inhibition of HRAS<sup>V12</sup> Expressing and Non-expressing Cell Lines by the Positive Control Compound RSL3 (CID 40911229) Identified in Pilot Screening</span></h3><div class="caption"><p>Growth inhibition concentration-response curves of RSL3 in engineered BJ fibroblasts expressing oncogenic HRas<sup>V12</sup> (BJeLR, DRD) or lacking HRas<sup>V12</sup> (BJeHLT, BJeH).</p></div></div></article><article data-type="fig" id="figobml162f9"><div id="ml162.f9" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162f9.jpg" alt="Scheme 1. Synthesis of the Probe." /></div><h3><span class="label">Scheme 1</span><span class="title">Synthesis of the Probe</span></h3></div></article><article data-type="fig" id="figobml162f5"><div id="ml162.f5" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162f5.jpg" alt="Figure 5. Stability Data for the Probe (CID 3689413/ML162) in PBS." /></div><h3><span class="label">Figure 5</span><span class="title">Stability Data for the Probe (CID 3689413/<a href="/pcsubstance/?term=ML162[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML162</a>) in PBS</span></h3><div class="caption"><p>Total ion count of the probe over time in PBS (blue line). Total ion count of the probe upon addition of acetonitrile (red line).</p></div></div></article><article data-type="fig" id="figobml162f6"><div id="ml162.f6" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162f6.jpg" alt="Figure 6. Racemic Mixture of the Probe (CID 3689413/ML162) in PBS." /></div><h3><span class="label">Figure 6</span><span class="title">Racemic Mixture of the Probe (CID 3689413/<a href="/pcsubstance/?term=ML162[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML162</a>) in PBS</span></h3><div class="caption"><p>Racemic mixture of the probe (CID 3689413/<a href="/pcsubstance/?term=ML162[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML162</a>) (<i>a</i>); single enantiomer A after purification on chiral HPLC (<i>b</i>); single enantiomer B after purification on chiral HPLC (<i>c</i>); and single enantiomer B after 48 hours incubation in PBS (<i>d</i>).</p></div></div></article><article data-type="table-wrap" id="figobml162t1"><div id="ml162.t1" class="table"><h3><span class="label">Table 1</span><span class="title">Summary of SAR on the Alpha-Chloroamide Portion</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK55069/table/ml162.t1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml162.t1_lrgtbl__"><table class="no_margin"><thead><tr><th id="hd_h_ml162.t1_1_1_1_1" colspan="4" rowspan="1" style="text-align:center;vertical-align:middle;">SAR Analysis on the α-Chloroamide Portion</th><th id="hd_h_ml162.t1_1_1_1_2" colspan="2" rowspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu3.jpg" alt="Image ml162fu3.jpg" /></div></th><th id="hd_h_ml162.t1_1_1_1_3" colspan="4" rowspan="1" style="text-align:center;vertical-align:middle;">Potency (μM) Mean ± S.E.M. (n=replicates)</th><th id="hd_h_ml162.t1_1_1_1_4" rowspan="3" colspan="1" headers="hd_h_ml162.t1_1_1_1_4" style="text-align:center;vertical-align:middle;">Target to Antitarget Fold Selectivity</th></tr><tr><th headers="hd_h_ml162.t1_1_1_1_1 hd_h_ml162.t1_1_1_2_1" id="hd_h_ml162.t1_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">No.</th><th headers="hd_h_ml162.t1_1_1_1_1 hd_h_ml162.t1_1_1_2_2" id="hd_h_ml162.t1_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CID</th><th headers="hd_h_ml162.t1_1_1_1_1 hd_h_ml162.t1_1_1_2_3" id="hd_h_ml162.t1_1_1_2_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">SID</th><th headers="hd_h_ml162.t1_1_1_1_1 hd_h_ml162.t1_1_1_2_4" id="hd_h_ml162.t1_1_1_2_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">Broad ID</th><th headers="hd_h_ml162.t1_1_1_1_2 hd_h_ml162.t1_1_1_2_5" id="hd_h_ml162.t1_1_1_2_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"><sup>*</sup></th><th headers="hd_h_ml162.t1_1_1_1_2 hd_h_ml162.t1_1_1_2_6" id="hd_h_ml162.t1_1_1_2_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">R<sub>1</sub></th><th headers="hd_h_ml162.t1_1_1_1_3" id="hd_h_ml162.t1_1_1_2_7" colspan="2" rowspan="1" style="text-align:center;vertical-align:middle;">BJeLR</th><th headers="hd_h_ml162.t1_1_1_1_3" id="hd_h_ml162.t1_1_1_2_8" colspan="2" rowspan="1" style="text-align:center;vertical-align:middle;">BJeH-LT</th></tr><tr><th headers="hd_h_ml162.t1_1_1_1_3 hd_h_ml162.t1_1_1_2_7" id="hd_h_ml162.t1_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">n</th><th headers="hd_h_ml162.t1_1_1_1_3 hd_h_ml162.t1_1_1_2_7" id="hd_h_ml162.t1_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IC<sub>50</sub></th><th headers="hd_h_ml162.t1_1_1_1_3 hd_h_ml162.t1_1_1_2_8" id="hd_h_ml162.t1_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">n</th><th headers="hd_h_ml162.t1_1_1_1_3 hd_h_ml162.t1_1_1_2_8" id="hd_h_ml162.t1_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IC<sub>50</sub></th></tr></thead><tbody><tr><td headers="hd_h_ml162.t1_1_1_1_1 hd_h_ml162.t1_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml162.t1_1_1_1_1 hd_h_ml162.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3689413</td><td headers="hd_h_ml162.t1_1_1_1_1 hd_h_ml162.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">99495782</td><td headers="hd_h_ml162.t1_1_1_1_1 hd_h_ml162.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-A36275421</td><td headers="hd_h_ml162.t1_1_1_1_2 hd_h_ml162.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml162.t1_1_1_1_2 hd_h_ml162.t1_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Cl</td><td headers="hd_h_ml162.t1_1_1_1_3 hd_h_ml162.t1_1_1_2_7 hd_h_ml162.t1_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml162.t1_1_1_1_3 hd_h_ml162.t1_1_1_2_7 hd_h_ml162.t1_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.025 ± 0.001</td><td headers="hd_h_ml162.t1_1_1_1_3 hd_h_ml162.t1_1_1_2_8 hd_h_ml162.t1_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml162.t1_1_1_1_3 hd_h_ml162.t1_1_1_2_8 hd_h_ml162.t1_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.578 ± 0.412</td><td headers="hd_h_ml162.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">23</td></tr><tr><td headers="hd_h_ml162.t1_1_1_1_1 hd_h_ml162.t1_1_1_2_2 hd_h_ml162.t1_1_1_2_3 hd_h_ml162.t1_1_1_2_4 hd_h_ml162.t1_1_1_1_2 hd_h_ml162.t1_1_1_2_5 hd_h_ml162.t1_1_1_2_6 hd_h_ml162.t1_1_1_1_3 hd_h_ml162.t1_1_1_2_7 hd_h_ml162.t1_1_1_3_1 hd_h_ml162.t1_1_1_3_2 hd_h_ml162.t1_1_1_2_8 hd_h_ml162.t1_1_1_3_3 hd_h_ml162.t1_1_1_3_4 hd_h_ml162.t1_1_1_1_4" colspan="10" rowspan="1" style="text-align:center;vertical-align:middle;">Solubility (PBS): <0.5 μM; PPB(h): 98.9%, (m): 99.1%; PS (h): 48.2%, (m) 9.4%; Purity: 95%</td></tr><tr><td headers="hd_h_ml162.t1_1_1_1_1 hd_h_ml162.t1_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml162.t1_1_1_1_1 hd_h_ml162.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">46897912</td><td headers="hd_h_ml162.t1_1_1_1_1 hd_h_ml162.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">99351091</td><td headers="hd_h_ml162.t1_1_1_1_1 hd_h_ml162.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-A77328124</td><td headers="hd_h_ml162.t1_1_1_1_2 hd_h_ml162.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml162.t1_1_1_1_2 hd_h_ml162.t1_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Me</td><td headers="hd_h_ml162.t1_1_1_1_3 hd_h_ml162.t1_1_1_2_7 hd_h_ml162.t1_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml162.t1_1_1_1_3 hd_h_ml162.t1_1_1_2_7 hd_h_ml162.t1_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml162.t1_1_1_1_3 hd_h_ml162.t1_1_1_2_8 hd_h_ml162.t1_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml162.t1_1_1_1_3 hd_h_ml162.t1_1_1_2_8 hd_h_ml162.t1_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml162.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NA</td></tr><tr><td headers="hd_h_ml162.t1_1_1_1_1 hd_h_ml162.t1_1_1_2_2 hd_h_ml162.t1_1_1_2_3 hd_h_ml162.t1_1_1_2_4 hd_h_ml162.t1_1_1_1_2 hd_h_ml162.t1_1_1_2_5 hd_h_ml162.t1_1_1_2_6 hd_h_ml162.t1_1_1_1_3 hd_h_ml162.t1_1_1_2_7 hd_h_ml162.t1_1_1_3_1 hd_h_ml162.t1_1_1_3_2 hd_h_ml162.t1_1_1_2_8 hd_h_ml162.t1_1_1_3_3 hd_h_ml162.t1_1_1_3_4 hd_h_ml162.t1_1_1_1_4" colspan="10" rowspan="1" style="text-align:center;vertical-align:middle;">Solubility (PBS): 2.9 μM; PPB(h): 98.9%, (m): 98.7%; PS (h): 99.9%, (m) 100%; Purity: 100%</td></tr><tr><td headers="hd_h_ml162.t1_1_1_1_1 hd_h_ml162.t1_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml162.t1_1_1_1_1 hd_h_ml162.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">46897909</td><td headers="hd_h_ml162.t1_1_1_1_1 hd_h_ml162.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">99351090</td><td headers="hd_h_ml162.t1_1_1_1_1 hd_h_ml162.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-A43322099</td><td headers="hd_h_ml162.t1_1_1_1_2 hd_h_ml162.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml162.t1_1_1_1_2 hd_h_ml162.t1_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">OMe</td><td headers="hd_h_ml162.t1_1_1_1_3 hd_h_ml162.t1_1_1_2_7 hd_h_ml162.t1_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml162.t1_1_1_1_3 hd_h_ml162.t1_1_1_2_7 hd_h_ml162.t1_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml162.t1_1_1_1_3 hd_h_ml162.t1_1_1_2_8 hd_h_ml162.t1_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml162.t1_1_1_1_3 hd_h_ml162.t1_1_1_2_8 hd_h_ml162.t1_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml162.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NA</td></tr><tr><td headers="hd_h_ml162.t1_1_1_1_1 hd_h_ml162.t1_1_1_2_2 hd_h_ml162.t1_1_1_2_3 hd_h_ml162.t1_1_1_2_4 hd_h_ml162.t1_1_1_1_2 hd_h_ml162.t1_1_1_2_5 hd_h_ml162.t1_1_1_2_6 hd_h_ml162.t1_1_1_1_3 hd_h_ml162.t1_1_1_2_7 hd_h_ml162.t1_1_1_3_1 hd_h_ml162.t1_1_1_3_2 hd_h_ml162.t1_1_1_2_8 hd_h_ml162.t1_1_1_3_3 hd_h_ml162.t1_1_1_3_4 hd_h_ml162.t1_1_1_1_4" colspan="10" rowspan="1" style="text-align:center;vertical-align:middle;">Solubility (PBS): 36.7 μM; PPB(h): 96.4%, (m): 96.2%; PS (h): 96.2%, (m) 100%; Purity: 100%</td></tr><tr><td headers="hd_h_ml162.t1_1_1_1_1 hd_h_ml162.t1_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml162.t1_1_1_1_1 hd_h_ml162.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">46897907</td><td headers="hd_h_ml162.t1_1_1_1_1 hd_h_ml162.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">99351088</td><td headers="hd_h_ml162.t1_1_1_1_1 hd_h_ml162.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-A28166528</td><td headers="hd_h_ml162.t1_1_1_1_2 hd_h_ml162.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml162.t1_1_1_1_2 hd_h_ml162.t1_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">OH</td><td headers="hd_h_ml162.t1_1_1_1_3 hd_h_ml162.t1_1_1_2_7 hd_h_ml162.t1_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml162.t1_1_1_1_3 hd_h_ml162.t1_1_1_2_7 hd_h_ml162.t1_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml162.t1_1_1_1_3 hd_h_ml162.t1_1_1_2_8 hd_h_ml162.t1_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml162.t1_1_1_1_3 hd_h_ml162.t1_1_1_2_8 hd_h_ml162.t1_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml162.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NA</td></tr><tr><td headers="hd_h_ml162.t1_1_1_1_1 hd_h_ml162.t1_1_1_2_2 hd_h_ml162.t1_1_1_2_3 hd_h_ml162.t1_1_1_2_4 hd_h_ml162.t1_1_1_1_2 hd_h_ml162.t1_1_1_2_5 hd_h_ml162.t1_1_1_2_6 hd_h_ml162.t1_1_1_1_3 hd_h_ml162.t1_1_1_2_7 hd_h_ml162.t1_1_1_3_1 hd_h_ml162.t1_1_1_3_2 hd_h_ml162.t1_1_1_2_8 hd_h_ml162.t1_1_1_3_3 hd_h_ml162.t1_1_1_3_4 hd_h_ml162.t1_1_1_1_4" colspan="10" rowspan="1" style="text-align:center;vertical-align:middle;">Solubility (PBS): 62.1 μM; PPB(h): 96.4%, (m): 96.3%; PS (h): 100%, (m) 100%; Purity: 100%</td></tr><tr><td headers="hd_h_ml162.t1_1_1_1_1 hd_h_ml162.t1_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">5</td><td headers="hd_h_ml162.t1_1_1_1_1 hd_h_ml162.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">49766533</td><td headers="hd_h_ml162.t1_1_1_1_1 hd_h_ml162.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">103023294</td><td headers="hd_h_ml162.t1_1_1_1_1 hd_h_ml162.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-A98134280</td><td headers="hd_h_ml162.t1_1_1_1_2 hd_h_ml162.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml162.t1_1_1_1_2 hd_h_ml162.t1_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu4.jpg" alt="Image ml162fu4.jpg" /></div></td><td headers="hd_h_ml162.t1_1_1_1_3 hd_h_ml162.t1_1_1_2_7 hd_h_ml162.t1_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml162.t1_1_1_1_3 hd_h_ml162.t1_1_1_2_7 hd_h_ml162.t1_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml162.t1_1_1_1_3 hd_h_ml162.t1_1_1_2_8 hd_h_ml162.t1_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml162.t1_1_1_1_3 hd_h_ml162.t1_1_1_2_8 hd_h_ml162.t1_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml162.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NA</td></tr><tr><td headers="hd_h_ml162.t1_1_1_1_1 hd_h_ml162.t1_1_1_2_2 hd_h_ml162.t1_1_1_2_3 hd_h_ml162.t1_1_1_2_4 hd_h_ml162.t1_1_1_1_2 hd_h_ml162.t1_1_1_2_5 hd_h_ml162.t1_1_1_2_6 hd_h_ml162.t1_1_1_1_3 hd_h_ml162.t1_1_1_2_7 hd_h_ml162.t1_1_1_3_1 hd_h_ml162.t1_1_1_3_2 hd_h_ml162.t1_1_1_2_8 hd_h_ml162.t1_1_1_3_3 hd_h_ml162.t1_1_1_3_4 hd_h_ml162.t1_1_1_1_4" colspan="10" rowspan="1" style="text-align:center;vertical-align:middle;">Solubility (PBS): <0.5 μM; PPB (h): 99.2%, (m): 99.1%; PS (h): 94.8%, (m) 85.5%; Purity: 95%</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>*</dt><dd><div id="ml162.tfn3"><p class="no_margin">P=Purchased; S=Synthesized.</p></div></dd></dl><dl class="bkr_refwrap"><dt></dt><dd><div id="ml162.tfn4"><p class="no_margin">IA=Inactive; m=mouse; NA=Not applicable; ND=Not determined; PPB(h)=Plasma protein binding in human; PS(h)=Plasma stability in human</p></div></dd></dl></dl></div></div></div></article><article data-type="fig" id="figobml162f7"><div id="ml162.f7" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%207.%20Critical%20Path%20for%20Probe%20Development.&p=BOOKS&id=55069_ml162f7.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK55069/bin/ml162f7.jpg" alt="Figure 7. Critical Path for Probe Development." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 7</span><span class="title">Critical Path for Probe Development</span></h3></div></article><article data-type="fig" id="figobml162f8"><div id="ml162.f8" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162f8.jpg" alt="Figure 8. Concentration-dependent Activities by the Probe (CID 3689413/ML162) in HRASV12 Expressing and Non-expressing Cell Lines." /></div><h3><span class="label">Figure 8</span><span class="title">Concentration-dependent Activities by the Probe (CID 3689413/<a href="/pcsubstance/?term=ML162[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML162</a>) in HRAS<sup>V12</sup> Expressing and Non-expressing Cell Lines</span></h3><div class="caption"><p>Activity curves for probe (CID 3689413/<a href="/pcsubstance/?term=ML162[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML162</a>): BJeLR (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2608" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2608</a>) (<i>a</i>); DRD (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2607" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2607</a>) (<i>b</i>); BJeH-LT (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2609" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2609</a>)(<i>c</i>); BJeH (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2611" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2611</a>)(<i>d</i>).</p></div></div></article><article data-type="table-wrap" id="figobml162t3"><div id="ml162.t3" class="table"><h3><span class="label">Table 3</span><span class="title">Summary of SAR on the Thiophene Portion</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK55069/table/ml162.t3/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml162.t3_lrgtbl__"><table class="no_margin"><thead><tr><th id="hd_h_ml162.t3_1_1_1_1" colspan="4" rowspan="1" style="text-align:center;vertical-align:middle;">SAR Analysis on the Thiophene Portion</th><th id="hd_h_ml162.t3_1_1_1_2" colspan="2" rowspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu5.jpg" alt="Image ml162fu5.jpg" /></div></th><th id="hd_h_ml162.t3_1_1_1_3" colspan="4" rowspan="1" style="text-align:center;vertical-align:middle;">Potency (μM) mean ± S.E.M. (n=replicates)</th><th id="hd_h_ml162.t3_1_1_1_4" rowspan="3" colspan="1" headers="hd_h_ml162.t3_1_1_1_4" style="text-align:center;vertical-align:middle;">Target to Antitarget Fold selectivity</th></tr><tr><th headers="hd_h_ml162.t3_1_1_1_1 hd_h_ml162.t3_1_1_2_1" id="hd_h_ml162.t3_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">No.</th><th headers="hd_h_ml162.t3_1_1_1_1 hd_h_ml162.t3_1_1_2_2" id="hd_h_ml162.t3_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CID</th><th headers="hd_h_ml162.t3_1_1_1_1 hd_h_ml162.t3_1_1_2_3" id="hd_h_ml162.t3_1_1_2_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">SID</th><th headers="hd_h_ml162.t3_1_1_1_1 hd_h_ml162.t3_1_1_2_4" id="hd_h_ml162.t3_1_1_2_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">Broad ID</th><th headers="hd_h_ml162.t3_1_1_1_2 hd_h_ml162.t3_1_1_2_5" id="hd_h_ml162.t3_1_1_2_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"><sup>*</sup></th><th headers="hd_h_ml162.t3_1_1_1_2 hd_h_ml162.t3_1_1_2_6" id="hd_h_ml162.t3_1_1_2_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">R<sub>1</sub></th><th headers="hd_h_ml162.t3_1_1_1_3" id="hd_h_ml162.t3_1_1_2_7" colspan="2" rowspan="1" style="text-align:center;vertical-align:middle;">BJeLR</th><th headers="hd_h_ml162.t3_1_1_1_3" id="hd_h_ml162.t3_1_1_2_8" colspan="2" rowspan="1" style="text-align:center;vertical-align:middle;">BJeH-LT</th></tr><tr><th headers="hd_h_ml162.t3_1_1_1_3 hd_h_ml162.t3_1_1_2_7" id="hd_h_ml162.t3_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">n</th><th headers="hd_h_ml162.t3_1_1_1_3 hd_h_ml162.t3_1_1_2_7" id="hd_h_ml162.t3_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IC<sub>50</sub></th><th headers="hd_h_ml162.t3_1_1_1_3 hd_h_ml162.t3_1_1_2_8" id="hd_h_ml162.t3_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">n</th><th headers="hd_h_ml162.t3_1_1_1_3 hd_h_ml162.t3_1_1_2_8" id="hd_h_ml162.t3_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IC<sub>50</sub></th></tr></thead><tbody><tr><td headers="hd_h_ml162.t3_1_1_1_1 hd_h_ml162.t3_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml162.t3_1_1_1_1 hd_h_ml162.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">46897904</td><td headers="hd_h_ml162.t3_1_1_1_1 hd_h_ml162.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">99351089</td><td headers="hd_h_ml162.t3_1_1_1_1 hd_h_ml162.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-A16737370</td><td headers="hd_h_ml162.t3_1_1_1_2 hd_h_ml162.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml162.t3_1_1_1_2 hd_h_ml162.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu6.jpg" alt="Image ml162fu6.jpg" /></div></td><td headers="hd_h_ml162.t3_1_1_1_3 hd_h_ml162.t3_1_1_2_7 hd_h_ml162.t3_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml162.t3_1_1_1_3 hd_h_ml162.t3_1_1_2_7 hd_h_ml162.t3_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.505</td><td headers="hd_h_ml162.t3_1_1_1_3 hd_h_ml162.t3_1_1_2_8 hd_h_ml162.t3_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml162.t3_1_1_1_3 hd_h_ml162.t3_1_1_2_8 hd_h_ml162.t3_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1.18</td><td headers="hd_h_ml162.t3_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2.3</td></tr><tr><td headers="hd_h_ml162.t3_1_1_1_1 hd_h_ml162.t3_1_1_2_2 hd_h_ml162.t3_1_1_2_3 hd_h_ml162.t3_1_1_2_4 hd_h_ml162.t3_1_1_1_2 hd_h_ml162.t3_1_1_2_5 hd_h_ml162.t3_1_1_2_6 hd_h_ml162.t3_1_1_1_3 hd_h_ml162.t3_1_1_2_7 hd_h_ml162.t3_1_1_3_1 hd_h_ml162.t3_1_1_3_2 hd_h_ml162.t3_1_1_2_8 hd_h_ml162.t3_1_1_3_3 hd_h_ml162.t3_1_1_3_4 hd_h_ml162.t3_1_1_1_4" colspan="10" rowspan="1" style="text-align:center;vertical-align:middle;">Solubility (PBS): <0.5 μM; PPB (h): 100%, (m): 89.1%; PS (h): 39.1%, (m) 8.8%; Purity: 89%</td></tr><tr><td headers="hd_h_ml162.t3_1_1_1_1 hd_h_ml162.t3_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml162.t3_1_1_1_1 hd_h_ml162.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">49766510</td><td headers="hd_h_ml162.t3_1_1_1_1 hd_h_ml162.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">103023291</td><td headers="hd_h_ml162.t3_1_1_1_1 hd_h_ml162.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-A50540937</td><td headers="hd_h_ml162.t3_1_1_1_2 hd_h_ml162.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml162.t3_1_1_1_2 hd_h_ml162.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu7.jpg" alt="Image ml162fu7.jpg" /></div></td><td headers="hd_h_ml162.t3_1_1_1_3 hd_h_ml162.t3_1_1_2_7 hd_h_ml162.t3_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml162.t3_1_1_1_3 hd_h_ml162.t3_1_1_2_7 hd_h_ml162.t3_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.895</td><td headers="hd_h_ml162.t3_1_1_1_3 hd_h_ml162.t3_1_1_2_8 hd_h_ml162.t3_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml162.t3_1_1_1_3 hd_h_ml162.t3_1_1_2_8 hd_h_ml162.t3_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1.3</td><td headers="hd_h_ml162.t3_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1.5</td></tr><tr><td headers="hd_h_ml162.t3_1_1_1_1 hd_h_ml162.t3_1_1_2_2 hd_h_ml162.t3_1_1_2_3 hd_h_ml162.t3_1_1_2_4 hd_h_ml162.t3_1_1_1_2 hd_h_ml162.t3_1_1_2_5 hd_h_ml162.t3_1_1_2_6 hd_h_ml162.t3_1_1_1_3 hd_h_ml162.t3_1_1_2_7 hd_h_ml162.t3_1_1_3_1 hd_h_ml162.t3_1_1_3_2 hd_h_ml162.t3_1_1_2_8 hd_h_ml162.t3_1_1_3_3 hd_h_ml162.t3_1_1_3_4 hd_h_ml162.t3_1_1_1_4" colspan="10" rowspan="1" style="text-align:center;vertical-align:middle;">Solubility (PBS): <0.5 μM; PPB (h): 95.5%, (m): 91.7%; PS (h): 51.8%, (m) 28.1%; Purity: 94%</td></tr><tr><td headers="hd_h_ml162.t3_1_1_1_1 hd_h_ml162.t3_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml162.t3_1_1_1_1 hd_h_ml162.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">49766537</td><td headers="hd_h_ml162.t3_1_1_1_1 hd_h_ml162.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">103023287</td><td headers="hd_h_ml162.t3_1_1_1_1 hd_h_ml162.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-A39023517</td><td headers="hd_h_ml162.t3_1_1_1_2 hd_h_ml162.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml162.t3_1_1_1_2 hd_h_ml162.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu8.jpg" alt="Image ml162fu8.jpg" /></div></td><td headers="hd_h_ml162.t3_1_1_1_3 hd_h_ml162.t3_1_1_2_7 hd_h_ml162.t3_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml162.t3_1_1_1_3 hd_h_ml162.t3_1_1_2_7 hd_h_ml162.t3_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">8.26</td><td headers="hd_h_ml162.t3_1_1_1_3 hd_h_ml162.t3_1_1_2_8 hd_h_ml162.t3_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml162.t3_1_1_1_3 hd_h_ml162.t3_1_1_2_8 hd_h_ml162.t3_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">19.8</td><td headers="hd_h_ml162.t3_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2.4</td></tr><tr><td headers="hd_h_ml162.t3_1_1_1_1 hd_h_ml162.t3_1_1_2_2 hd_h_ml162.t3_1_1_2_3 hd_h_ml162.t3_1_1_2_4 hd_h_ml162.t3_1_1_1_2 hd_h_ml162.t3_1_1_2_5 hd_h_ml162.t3_1_1_2_6 hd_h_ml162.t3_1_1_1_3 hd_h_ml162.t3_1_1_2_7 hd_h_ml162.t3_1_1_3_1 hd_h_ml162.t3_1_1_3_2 hd_h_ml162.t3_1_1_2_8 hd_h_ml162.t3_1_1_3_3 hd_h_ml162.t3_1_1_3_4 hd_h_ml162.t3_1_1_1_4" colspan="10" rowspan="1" style="text-align:center;vertical-align:middle;">Solubility (PBS): <0.5 μM; PPB (h): 98.4%, (m): 89.4%; PS (h): 97.4%, (m) 20.8%; Purity: 95%</td></tr><tr><td headers="hd_h_ml162.t3_1_1_1_1 hd_h_ml162.t3_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml162.t3_1_1_1_1 hd_h_ml162.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">49766511</td><td headers="hd_h_ml162.t3_1_1_1_1 hd_h_ml162.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">103023273</td><td headers="hd_h_ml162.t3_1_1_1_1 hd_h_ml162.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-A13066870</td><td headers="hd_h_ml162.t3_1_1_1_2 hd_h_ml162.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml162.t3_1_1_1_2 hd_h_ml162.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu9.jpg" alt="Image ml162fu9.jpg" /></div></td><td headers="hd_h_ml162.t3_1_1_1_3 hd_h_ml162.t3_1_1_2_7 hd_h_ml162.t3_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml162.t3_1_1_1_3 hd_h_ml162.t3_1_1_2_7 hd_h_ml162.t3_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.061</td><td headers="hd_h_ml162.t3_1_1_1_3 hd_h_ml162.t3_1_1_2_8 hd_h_ml162.t3_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml162.t3_1_1_1_3 hd_h_ml162.t3_1_1_2_8 hd_h_ml162.t3_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.133</td><td headers="hd_h_ml162.t3_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2.2</td></tr><tr><td headers="hd_h_ml162.t3_1_1_1_1 hd_h_ml162.t3_1_1_2_2 hd_h_ml162.t3_1_1_2_3 hd_h_ml162.t3_1_1_2_4 hd_h_ml162.t3_1_1_1_2 hd_h_ml162.t3_1_1_2_5 hd_h_ml162.t3_1_1_2_6 hd_h_ml162.t3_1_1_1_3 hd_h_ml162.t3_1_1_2_7 hd_h_ml162.t3_1_1_3_1 hd_h_ml162.t3_1_1_3_2 hd_h_ml162.t3_1_1_2_8 hd_h_ml162.t3_1_1_3_3 hd_h_ml162.t3_1_1_3_4 hd_h_ml162.t3_1_1_1_4" colspan="10" rowspan="1" style="text-align:center;vertical-align:middle;">Solubility (PBS): <0.5 μM; PPB (h): 99.7%, (m): 64.8%; PS (h): 32.2%, (m) 10.1%; Purity: 92%</td></tr><tr><td headers="hd_h_ml162.t3_1_1_1_1 hd_h_ml162.t3_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">5</td><td headers="hd_h_ml162.t3_1_1_1_1 hd_h_ml162.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">49766514</td><td headers="hd_h_ml162.t3_1_1_1_1 hd_h_ml162.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">103023292</td><td headers="hd_h_ml162.t3_1_1_1_1 hd_h_ml162.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-K59708724</td><td headers="hd_h_ml162.t3_1_1_1_2 hd_h_ml162.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml162.t3_1_1_1_2 hd_h_ml162.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu10.jpg" alt="Image ml162fu10.jpg" /></div></td><td headers="hd_h_ml162.t3_1_1_1_3 hd_h_ml162.t3_1_1_2_7 hd_h_ml162.t3_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml162.t3_1_1_1_3 hd_h_ml162.t3_1_1_2_7 hd_h_ml162.t3_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.231</td><td headers="hd_h_ml162.t3_1_1_1_3 hd_h_ml162.t3_1_1_2_8 hd_h_ml162.t3_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml162.t3_1_1_1_3 hd_h_ml162.t3_1_1_2_8 hd_h_ml162.t3_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.531</td><td headers="hd_h_ml162.t3_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2.3</td></tr><tr><td headers="hd_h_ml162.t3_1_1_1_1 hd_h_ml162.t3_1_1_2_2 hd_h_ml162.t3_1_1_2_3 hd_h_ml162.t3_1_1_2_4 hd_h_ml162.t3_1_1_1_2 hd_h_ml162.t3_1_1_2_5 hd_h_ml162.t3_1_1_2_6 hd_h_ml162.t3_1_1_1_3 hd_h_ml162.t3_1_1_2_7 hd_h_ml162.t3_1_1_3_1 hd_h_ml162.t3_1_1_3_2 hd_h_ml162.t3_1_1_2_8 hd_h_ml162.t3_1_1_3_3 hd_h_ml162.t3_1_1_3_4 hd_h_ml162.t3_1_1_1_4" colspan="10" rowspan="1" style="text-align:center;vertical-align:middle;">Solubility (PBS): 23.3 μM; PPB (h): 0%, (m): 85.0%; PS (h): 0.7%, (m) 2.0%; Purity: 90%</td></tr><tr><td headers="hd_h_ml162.t3_1_1_1_1 hd_h_ml162.t3_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">6</td><td headers="hd_h_ml162.t3_1_1_1_1 hd_h_ml162.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">49766515</td><td headers="hd_h_ml162.t3_1_1_1_1 hd_h_ml162.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">103023289</td><td headers="hd_h_ml162.t3_1_1_1_1 hd_h_ml162.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-K55411940</td><td headers="hd_h_ml162.t3_1_1_1_2 hd_h_ml162.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml162.t3_1_1_1_2 hd_h_ml162.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu11.jpg" alt="Image ml162fu11.jpg" /></div></td><td headers="hd_h_ml162.t3_1_1_1_3 hd_h_ml162.t3_1_1_2_7 hd_h_ml162.t3_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml162.t3_1_1_1_3 hd_h_ml162.t3_1_1_2_7 hd_h_ml162.t3_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.058</td><td headers="hd_h_ml162.t3_1_1_1_3 hd_h_ml162.t3_1_1_2_8 hd_h_ml162.t3_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml162.t3_1_1_1_3 hd_h_ml162.t3_1_1_2_8 hd_h_ml162.t3_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.127</td><td headers="hd_h_ml162.t3_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2.2</td></tr><tr><td headers="hd_h_ml162.t3_1_1_1_1 hd_h_ml162.t3_1_1_2_2 hd_h_ml162.t3_1_1_2_3 hd_h_ml162.t3_1_1_2_4 hd_h_ml162.t3_1_1_1_2 hd_h_ml162.t3_1_1_2_5 hd_h_ml162.t3_1_1_2_6 hd_h_ml162.t3_1_1_1_3 hd_h_ml162.t3_1_1_2_7 hd_h_ml162.t3_1_1_3_1 hd_h_ml162.t3_1_1_3_2 hd_h_ml162.t3_1_1_2_8 hd_h_ml162.t3_1_1_3_3 hd_h_ml162.t3_1_1_3_4 hd_h_ml162.t3_1_1_1_4" colspan="10" rowspan="1" style="text-align:center;vertical-align:middle;">Solubility (PBS): 11.6 μM; PPB (h): 90.8%, (m): 78.8%; PS (h): 69.2%, (m) 27.3%; Purity: 91%</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>*</dt><dd><div id="ml162.tfn5"><p class="no_margin">P=Purchased; S=Synthesized.</p></div></dd></dl><dl class="bkr_refwrap"><dt></dt><dd><div id="ml162.tfn6"><p class="no_margin">IA=Inactive; m=mouse; ND=Not determined; PPB (h)=Plasma protein binding in human; PS (h)=Plasma stability in human</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobml162t4"><div id="ml162.t4" class="table"><h3><span class="label">Table 4</span><span class="title">Summary of SAR on the Phenethylamine Portion</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK55069/table/ml162.t4/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml162.t4_lrgtbl__"><table class="no_margin"><thead><tr><th id="hd_h_ml162.t4_1_1_1_1" colspan="4" rowspan="1" style="text-align:center;vertical-align:middle;">SAR Analysis on the Phenethylamine Portion</th><th id="hd_h_ml162.t4_1_1_1_2" colspan="2" rowspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu12.jpg" alt="Image ml162fu12.jpg" /></div></th><th id="hd_h_ml162.t4_1_1_1_3" colspan="4" rowspan="1" style="text-align:center;vertical-align:middle;">Potency (μM) mean ± S.E.M. (n=replicates)</th><th id="hd_h_ml162.t4_1_1_1_4" rowspan="3" colspan="1" headers="hd_h_ml162.t4_1_1_1_4" style="text-align:center;vertical-align:middle;">Target to Antitarget Fold selectivity</th></tr><tr><th headers="hd_h_ml162.t4_1_1_1_1 hd_h_ml162.t4_1_1_2_1" id="hd_h_ml162.t4_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">No.</th><th headers="hd_h_ml162.t4_1_1_1_1 hd_h_ml162.t4_1_1_2_2" id="hd_h_ml162.t4_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CID</th><th headers="hd_h_ml162.t4_1_1_1_1 hd_h_ml162.t4_1_1_2_3" id="hd_h_ml162.t4_1_1_2_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">SID</th><th headers="hd_h_ml162.t4_1_1_1_1 hd_h_ml162.t4_1_1_2_4" id="hd_h_ml162.t4_1_1_2_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">Broad ID</th><th headers="hd_h_ml162.t4_1_1_1_2 hd_h_ml162.t4_1_1_2_5" id="hd_h_ml162.t4_1_1_2_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"><sup>*</sup></th><th headers="hd_h_ml162.t4_1_1_1_2 hd_h_ml162.t4_1_1_2_6" id="hd_h_ml162.t4_1_1_2_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">R<sub>1</sub></th><th headers="hd_h_ml162.t4_1_1_1_3" id="hd_h_ml162.t4_1_1_2_7" colspan="2" rowspan="1" style="text-align:center;vertical-align:middle;">BJeLR</th><th headers="hd_h_ml162.t4_1_1_1_3" id="hd_h_ml162.t4_1_1_2_8" colspan="2" rowspan="1" style="text-align:center;vertical-align:middle;">BJeH-LT</th></tr><tr><th headers="hd_h_ml162.t4_1_1_1_3 hd_h_ml162.t4_1_1_2_7" id="hd_h_ml162.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">n</th><th headers="hd_h_ml162.t4_1_1_1_3 hd_h_ml162.t4_1_1_2_7" id="hd_h_ml162.t4_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IC<sub>50</sub></th><th headers="hd_h_ml162.t4_1_1_1_3 hd_h_ml162.t4_1_1_2_8" id="hd_h_ml162.t4_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">n</th><th headers="hd_h_ml162.t4_1_1_1_3 hd_h_ml162.t4_1_1_2_8" id="hd_h_ml162.t4_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IC<sub>50</sub></th></tr></thead><tbody><tr><td headers="hd_h_ml162.t4_1_1_1_1 hd_h_ml162.t4_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml162.t4_1_1_1_1 hd_h_ml162.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5062094</td><td headers="hd_h_ml162.t4_1_1_1_1 hd_h_ml162.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">99351087</td><td headers="hd_h_ml162.t4_1_1_1_1 hd_h_ml162.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-A95371206</td><td headers="hd_h_ml162.t4_1_1_1_2 hd_h_ml162.t4_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml162.t4_1_1_1_2 hd_h_ml162.t4_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu13.jpg" alt="Image ml162fu13.jpg" /></div></td><td headers="hd_h_ml162.t4_1_1_1_3 hd_h_ml162.t4_1_1_2_7 hd_h_ml162.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml162.t4_1_1_1_3 hd_h_ml162.t4_1_1_2_7 hd_h_ml162.t4_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.113</td><td headers="hd_h_ml162.t4_1_1_1_3 hd_h_ml162.t4_1_1_2_8 hd_h_ml162.t4_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml162.t4_1_1_1_3 hd_h_ml162.t4_1_1_2_8 hd_h_ml162.t4_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.270</td><td headers="hd_h_ml162.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2.4</td></tr><tr><td headers="hd_h_ml162.t4_1_1_1_1 hd_h_ml162.t4_1_1_2_2 hd_h_ml162.t4_1_1_2_3 hd_h_ml162.t4_1_1_2_4 hd_h_ml162.t4_1_1_1_2 hd_h_ml162.t4_1_1_2_5 hd_h_ml162.t4_1_1_2_6 hd_h_ml162.t4_1_1_1_3 hd_h_ml162.t4_1_1_2_7 hd_h_ml162.t4_1_1_3_1 hd_h_ml162.t4_1_1_3_2 hd_h_ml162.t4_1_1_2_8 hd_h_ml162.t4_1_1_3_3 hd_h_ml162.t4_1_1_3_4 hd_h_ml162.t4_1_1_1_4" colspan="10" rowspan="1" style="text-align:center;vertical-align:middle;">Solubility (PBS): <0.5 μM; PPB (h): 98.2%, (m): 95.6%; PS (h): 37.9%, (m) 1.4%; Purity: 90%</td></tr><tr><td headers="hd_h_ml162.t4_1_1_1_1 hd_h_ml162.t4_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml162.t4_1_1_1_1 hd_h_ml162.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">49766544</td><td headers="hd_h_ml162.t4_1_1_1_1 hd_h_ml162.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">103023284</td><td headers="hd_h_ml162.t4_1_1_1_1 hd_h_ml162.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-A35556600</td><td headers="hd_h_ml162.t4_1_1_1_2 hd_h_ml162.t4_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml162.t4_1_1_1_2 hd_h_ml162.t4_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu14.jpg" alt="Image ml162fu14.jpg" /></div></td><td headers="hd_h_ml162.t4_1_1_1_3 hd_h_ml162.t4_1_1_2_7 hd_h_ml162.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml162.t4_1_1_1_3 hd_h_ml162.t4_1_1_2_7 hd_h_ml162.t4_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.075</td><td headers="hd_h_ml162.t4_1_1_1_3 hd_h_ml162.t4_1_1_2_8 hd_h_ml162.t4_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml162.t4_1_1_1_3 hd_h_ml162.t4_1_1_2_8 hd_h_ml162.t4_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.179</td><td headers="hd_h_ml162.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2.4</td></tr><tr><td headers="hd_h_ml162.t4_1_1_1_1 hd_h_ml162.t4_1_1_2_2 hd_h_ml162.t4_1_1_2_3 hd_h_ml162.t4_1_1_2_4 hd_h_ml162.t4_1_1_1_2 hd_h_ml162.t4_1_1_2_5 hd_h_ml162.t4_1_1_2_6 hd_h_ml162.t4_1_1_1_3 hd_h_ml162.t4_1_1_2_7 hd_h_ml162.t4_1_1_3_1 hd_h_ml162.t4_1_1_3_2 hd_h_ml162.t4_1_1_2_8 hd_h_ml162.t4_1_1_3_3 hd_h_ml162.t4_1_1_3_4 hd_h_ml162.t4_1_1_1_4" colspan="10" rowspan="1" style="text-align:center;vertical-align:middle;">Solubility (PBS): <0.5 μM; PPB (h): 98.0%, (m): 96.0%; PS (h): 37.7%, (m) 9.7%; Purity: 94%</td></tr><tr><td headers="hd_h_ml162.t4_1_1_1_1 hd_h_ml162.t4_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml162.t4_1_1_1_1 hd_h_ml162.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">49766532</td><td headers="hd_h_ml162.t4_1_1_1_1 hd_h_ml162.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">103023285</td><td headers="hd_h_ml162.t4_1_1_1_1 hd_h_ml162.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-A16084367</td><td headers="hd_h_ml162.t4_1_1_1_2 hd_h_ml162.t4_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml162.t4_1_1_1_2 hd_h_ml162.t4_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu15.jpg" alt="Image ml162fu15.jpg" /></div></td><td headers="hd_h_ml162.t4_1_1_1_3 hd_h_ml162.t4_1_1_2_7 hd_h_ml162.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml162.t4_1_1_1_3 hd_h_ml162.t4_1_1_2_7 hd_h_ml162.t4_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.089</td><td headers="hd_h_ml162.t4_1_1_1_3 hd_h_ml162.t4_1_1_2_8 hd_h_ml162.t4_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml162.t4_1_1_1_3 hd_h_ml162.t4_1_1_2_8 hd_h_ml162.t4_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.208</td><td headers="hd_h_ml162.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2.3</td></tr><tr><td headers="hd_h_ml162.t4_1_1_1_1 hd_h_ml162.t4_1_1_2_2 hd_h_ml162.t4_1_1_2_3 hd_h_ml162.t4_1_1_2_4 hd_h_ml162.t4_1_1_1_2 hd_h_ml162.t4_1_1_2_5 hd_h_ml162.t4_1_1_2_6 hd_h_ml162.t4_1_1_1_3 hd_h_ml162.t4_1_1_2_7 hd_h_ml162.t4_1_1_3_1 hd_h_ml162.t4_1_1_3_2 hd_h_ml162.t4_1_1_2_8 hd_h_ml162.t4_1_1_3_3 hd_h_ml162.t4_1_1_3_4 hd_h_ml162.t4_1_1_1_4" colspan="10" rowspan="1" style="text-align:center;vertical-align:middle;">Solubility (PBS): 16.2 μM; PPB (h): ND, (m): ND; PS (h): ND, (m) ND; Purity: 94%</td></tr><tr><td headers="hd_h_ml162.t4_1_1_1_1 hd_h_ml162.t4_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml162.t4_1_1_1_1 hd_h_ml162.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">49766508</td><td headers="hd_h_ml162.t4_1_1_1_1 hd_h_ml162.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">103023271</td><td headers="hd_h_ml162.t4_1_1_1_1 hd_h_ml162.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-A66597842</td><td headers="hd_h_ml162.t4_1_1_1_2 hd_h_ml162.t4_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml162.t4_1_1_1_2 hd_h_ml162.t4_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu16.jpg" alt="Image ml162fu16.jpg" /></div></td><td headers="hd_h_ml162.t4_1_1_1_3 hd_h_ml162.t4_1_1_2_7 hd_h_ml162.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml162.t4_1_1_1_3 hd_h_ml162.t4_1_1_2_7 hd_h_ml162.t4_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.102</td><td headers="hd_h_ml162.t4_1_1_1_3 hd_h_ml162.t4_1_1_2_8 hd_h_ml162.t4_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml162.t4_1_1_1_3 hd_h_ml162.t4_1_1_2_8 hd_h_ml162.t4_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.242</td><td headers="hd_h_ml162.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2.4</td></tr><tr><td headers="hd_h_ml162.t4_1_1_1_1 hd_h_ml162.t4_1_1_2_2 hd_h_ml162.t4_1_1_2_3 hd_h_ml162.t4_1_1_2_4 hd_h_ml162.t4_1_1_1_2 hd_h_ml162.t4_1_1_2_5 hd_h_ml162.t4_1_1_2_6 hd_h_ml162.t4_1_1_1_3 hd_h_ml162.t4_1_1_2_7 hd_h_ml162.t4_1_1_3_1 hd_h_ml162.t4_1_1_3_2 hd_h_ml162.t4_1_1_2_8 hd_h_ml162.t4_1_1_3_3 hd_h_ml162.t4_1_1_3_4 hd_h_ml162.t4_1_1_1_4" colspan="10" rowspan="1" style="text-align:center;vertical-align:middle;">Solubility (PBS): <0.5 μM; PPB (h): 70.9%, (m): 40.3%; PS (h): 7.7%, (m) 0%; Purity: 89%</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>*</dt><dd><div id="ml162.tfn7"><p class="no_margin">P=Purchased; S=Synthesized.</p></div></dd></dl><dl class="bkr_refwrap"><dt></dt><dd><div id="ml162.tfn8"><p class="no_margin">IA=Inactive; m=mouse; ND=Not determined; PPB (h)=Plasma protein binding in human; PS (h)=Plasma stability in human</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobml162t5"><div id="ml162.t5" class="table"><h3><span class="label">Table 5</span><span class="title">Summary of SAR for Other Alpha-Chloroamide Analogs</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK55069/table/ml162.t5/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml162.t5_lrgtbl__"><table class="no_margin"><thead><tr><th id="hd_h_ml162.t5_1_1_1_1" colspan="5" rowspan="1" style="text-align:center;vertical-align:middle;">SAR Analysis for Other Alpha-Chloroamide Analogs</th><th id="hd_h_ml162.t5_1_1_1_2" rowspan="3" colspan="1" headers="hd_h_ml162.t5_1_1_1_2" style="text-align:center;vertical-align:middle;">Structure</th><th id="hd_h_ml162.t5_1_1_1_3" colspan="4" rowspan="1" style="text-align:center;vertical-align:middle;">Potency (μM)mean ± S.E.M. (n=replicates)</th><th id="hd_h_ml162.t5_1_1_1_4" rowspan="3" colspan="1" headers="hd_h_ml162.t5_1_1_1_4" style="text-align:center;vertical-align:middle;">Target to Antitarget Fold selectivity</th></tr><tr><th headers="hd_h_ml162.t5_1_1_1_1 hd_h_ml162.t5_1_1_2_1" id="hd_h_ml162.t5_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">No.</th><th headers="hd_h_ml162.t5_1_1_1_1 hd_h_ml162.t5_1_1_2_2" id="hd_h_ml162.t5_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CID</th><th headers="hd_h_ml162.t5_1_1_1_1 hd_h_ml162.t5_1_1_2_3" id="hd_h_ml162.t5_1_1_2_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">SID</th><th headers="hd_h_ml162.t5_1_1_1_1 hd_h_ml162.t5_1_1_2_4" id="hd_h_ml162.t5_1_1_2_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">Broad ID</th><th headers="hd_h_ml162.t5_1_1_1_1 hd_h_ml162.t5_1_1_2_5" id="hd_h_ml162.t5_1_1_2_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"><sup>*</sup></th><th headers="hd_h_ml162.t5_1_1_1_3" id="hd_h_ml162.t5_1_1_2_6" colspan="2" rowspan="1" style="text-align:center;vertical-align:middle;">BJeLR</th><th headers="hd_h_ml162.t5_1_1_1_3" id="hd_h_ml162.t5_1_1_2_7" colspan="2" rowspan="1" style="text-align:center;vertical-align:middle;">BJeH-LT</th></tr><tr><th headers="hd_h_ml162.t5_1_1_1_3 hd_h_ml162.t5_1_1_2_6" id="hd_h_ml162.t5_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">n</th><th headers="hd_h_ml162.t5_1_1_1_3 hd_h_ml162.t5_1_1_2_6" id="hd_h_ml162.t5_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IC<sub>50</sub></th><th headers="hd_h_ml162.t5_1_1_1_3 hd_h_ml162.t5_1_1_2_7" id="hd_h_ml162.t5_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">n</th><th headers="hd_h_ml162.t5_1_1_1_3 hd_h_ml162.t5_1_1_2_7" id="hd_h_ml162.t5_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IC<sub>50</sub></th></tr></thead><tbody><tr><td headers="hd_h_ml162.t5_1_1_1_1 hd_h_ml162.t5_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml162.t5_1_1_1_1 hd_h_ml162.t5_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">46897910</td><td headers="hd_h_ml162.t5_1_1_1_1 hd_h_ml162.t5_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">99351086</td><td headers="hd_h_ml162.t5_1_1_1_1 hd_h_ml162.t5_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-A78541818</td><td headers="hd_h_ml162.t5_1_1_1_1 hd_h_ml162.t5_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml162.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu17.jpg" alt="Image ml162fu17.jpg" /></div></td><td headers="hd_h_ml162.t5_1_1_1_3 hd_h_ml162.t5_1_1_2_6 hd_h_ml162.t5_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml162.t5_1_1_1_3 hd_h_ml162.t5_1_1_2_6 hd_h_ml162.t5_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.122</td><td headers="hd_h_ml162.t5_1_1_1_3 hd_h_ml162.t5_1_1_2_7 hd_h_ml162.t5_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml162.t5_1_1_1_3 hd_h_ml162.t5_1_1_2_7 hd_h_ml162.t5_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.366</td><td headers="hd_h_ml162.t5_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3.0</td></tr><tr><td headers="hd_h_ml162.t5_1_1_1_1 hd_h_ml162.t5_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml162.t5_1_1_1_1 hd_h_ml162.t5_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4381125</td><td headers="hd_h_ml162.t5_1_1_1_1 hd_h_ml162.t5_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">99495781</td><td headers="hd_h_ml162.t5_1_1_1_1 hd_h_ml162.t5_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-A76490030</td><td headers="hd_h_ml162.t5_1_1_1_1 hd_h_ml162.t5_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml162.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu18.jpg" alt="Image ml162fu18.jpg" /></div></td><td headers="hd_h_ml162.t5_1_1_1_3 hd_h_ml162.t5_1_1_2_6 hd_h_ml162.t5_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml162.t5_1_1_1_3 hd_h_ml162.t5_1_1_2_6 hd_h_ml162.t5_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.16</td><td headers="hd_h_ml162.t5_1_1_1_3 hd_h_ml162.t5_1_1_2_7 hd_h_ml162.t5_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml162.t5_1_1_1_3 hd_h_ml162.t5_1_1_2_7 hd_h_ml162.t5_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1.4</td><td headers="hd_h_ml162.t5_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">8.7</td></tr><tr><td headers="hd_h_ml162.t5_1_1_1_1 hd_h_ml162.t5_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml162.t5_1_1_1_1 hd_h_ml162.t5_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4230741</td><td headers="hd_h_ml162.t5_1_1_1_1 hd_h_ml162.t5_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">87692469</td><td headers="hd_h_ml162.t5_1_1_1_1 hd_h_ml162.t5_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-A11909039</td><td headers="hd_h_ml162.t5_1_1_1_1 hd_h_ml162.t5_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml162.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu19.jpg" alt="Image ml162fu19.jpg" /></div></td><td headers="hd_h_ml162.t5_1_1_1_3 hd_h_ml162.t5_1_1_2_6 hd_h_ml162.t5_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml162.t5_1_1_1_3 hd_h_ml162.t5_1_1_2_6 hd_h_ml162.t5_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.16</td><td headers="hd_h_ml162.t5_1_1_1_3 hd_h_ml162.t5_1_1_2_7 hd_h_ml162.t5_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml162.t5_1_1_1_3 hd_h_ml162.t5_1_1_2_7 hd_h_ml162.t5_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">8.3</td><td headers="hd_h_ml162.t5_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">52</td></tr><tr><td headers="hd_h_ml162.t5_1_1_1_1 hd_h_ml162.t5_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml162.t5_1_1_1_1 hd_h_ml162.t5_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2449454</td><td headers="hd_h_ml162.t5_1_1_1_1 hd_h_ml162.t5_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">99495785</td><td headers="hd_h_ml162.t5_1_1_1_1 hd_h_ml162.t5_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-K68313733</td><td headers="hd_h_ml162.t5_1_1_1_1 hd_h_ml162.t5_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml162.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu20.jpg" alt="Image ml162fu20.jpg" /></div></td><td headers="hd_h_ml162.t5_1_1_1_3 hd_h_ml162.t5_1_1_2_6 hd_h_ml162.t5_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml162.t5_1_1_1_3 hd_h_ml162.t5_1_1_2_6 hd_h_ml162.t5_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.85</td><td headers="hd_h_ml162.t5_1_1_1_3 hd_h_ml162.t5_1_1_2_7 hd_h_ml162.t5_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml162.t5_1_1_1_3 hd_h_ml162.t5_1_1_2_7 hd_h_ml162.t5_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">7.7</td><td headers="hd_h_ml162.t5_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">9</td></tr><tr><td headers="hd_h_ml162.t5_1_1_1_1 hd_h_ml162.t5_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5</td><td headers="hd_h_ml162.t5_1_1_1_1 hd_h_ml162.t5_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2416356</td><td headers="hd_h_ml162.t5_1_1_1_1 hd_h_ml162.t5_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">87692481</td><td headers="hd_h_ml162.t5_1_1_1_1 hd_h_ml162.t5_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-K62459624</td><td headers="hd_h_ml162.t5_1_1_1_1 hd_h_ml162.t5_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml162.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu21.jpg" alt="Image ml162fu21.jpg" /></div></td><td headers="hd_h_ml162.t5_1_1_1_3 hd_h_ml162.t5_1_1_2_6 hd_h_ml162.t5_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml162.t5_1_1_1_3 hd_h_ml162.t5_1_1_2_6 hd_h_ml162.t5_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.15</td><td headers="hd_h_ml162.t5_1_1_1_3 hd_h_ml162.t5_1_1_2_7 hd_h_ml162.t5_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml162.t5_1_1_1_3 hd_h_ml162.t5_1_1_2_7 hd_h_ml162.t5_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4.9</td><td headers="hd_h_ml162.t5_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">33</td></tr><tr><td headers="hd_h_ml162.t5_1_1_1_1 hd_h_ml162.t5_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6</td><td headers="hd_h_ml162.t5_1_1_1_1 hd_h_ml162.t5_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6545175</td><td headers="hd_h_ml162.t5_1_1_1_1 hd_h_ml162.t5_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">99495787</td><td headers="hd_h_ml162.t5_1_1_1_1 hd_h_ml162.t5_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-K78062244</td><td headers="hd_h_ml162.t5_1_1_1_1 hd_h_ml162.t5_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml162.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu22.jpg" alt="Image ml162fu22.jpg" /></div></td><td headers="hd_h_ml162.t5_1_1_1_3 hd_h_ml162.t5_1_1_2_6 hd_h_ml162.t5_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml162.t5_1_1_1_3 hd_h_ml162.t5_1_1_2_6 hd_h_ml162.t5_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.47</td><td headers="hd_h_ml162.t5_1_1_1_3 hd_h_ml162.t5_1_1_2_7 hd_h_ml162.t5_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml162.t5_1_1_1_3 hd_h_ml162.t5_1_1_2_7 hd_h_ml162.t5_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4.0</td><td headers="hd_h_ml162.t5_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">8.4</td></tr><tr><td headers="hd_h_ml162.t5_1_1_1_1 hd_h_ml162.t5_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">7</td><td headers="hd_h_ml162.t5_1_1_1_1 hd_h_ml162.t5_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1637653</td><td headers="hd_h_ml162.t5_1_1_1_1 hd_h_ml162.t5_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">99495788</td><td headers="hd_h_ml162.t5_1_1_1_1 hd_h_ml162.t5_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-K19499941</td><td headers="hd_h_ml162.t5_1_1_1_1 hd_h_ml162.t5_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml162.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu23.jpg" alt="Image ml162fu23.jpg" /></div></td><td headers="hd_h_ml162.t5_1_1_1_3 hd_h_ml162.t5_1_1_2_6 hd_h_ml162.t5_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml162.t5_1_1_1_3 hd_h_ml162.t5_1_1_2_6 hd_h_ml162.t5_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.12</td><td headers="hd_h_ml162.t5_1_1_1_3 hd_h_ml162.t5_1_1_2_7 hd_h_ml162.t5_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml162.t5_1_1_1_3 hd_h_ml162.t5_1_1_2_7 hd_h_ml162.t5_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3.4</td><td headers="hd_h_ml162.t5_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">29</td></tr><tr><td headers="hd_h_ml162.t5_1_1_1_1 hd_h_ml162.t5_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">8</td><td headers="hd_h_ml162.t5_1_1_1_1 hd_h_ml162.t5_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2345373</td><td headers="hd_h_ml162.t5_1_1_1_1 hd_h_ml162.t5_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">99495789</td><td headers="hd_h_ml162.t5_1_1_1_1 hd_h_ml162.t5_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-K65258912</td><td headers="hd_h_ml162.t5_1_1_1_1 hd_h_ml162.t5_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml162.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu24.jpg" alt="Image ml162fu24.jpg" /></div></td><td headers="hd_h_ml162.t5_1_1_1_3 hd_h_ml162.t5_1_1_2_6 hd_h_ml162.t5_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml162.t5_1_1_1_3 hd_h_ml162.t5_1_1_2_6 hd_h_ml162.t5_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml162.t5_1_1_1_3 hd_h_ml162.t5_1_1_2_7 hd_h_ml162.t5_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml162.t5_1_1_1_3 hd_h_ml162.t5_1_1_2_7 hd_h_ml162.t5_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml162.t5_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NA</td></tr><tr><td headers="hd_h_ml162.t5_1_1_1_1 hd_h_ml162.t5_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">9</td><td headers="hd_h_ml162.t5_1_1_1_1 hd_h_ml162.t5_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">566661</td><td headers="hd_h_ml162.t5_1_1_1_1 hd_h_ml162.t5_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">89856185</td><td headers="hd_h_ml162.t5_1_1_1_1 hd_h_ml162.t5_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-K48576794</td><td headers="hd_h_ml162.t5_1_1_1_1 hd_h_ml162.t5_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml162.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu25.jpg" alt="Image ml162fu25.jpg" /></div></td><td headers="hd_h_ml162.t5_1_1_1_3 hd_h_ml162.t5_1_1_2_6 hd_h_ml162.t5_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml162.t5_1_1_1_3 hd_h_ml162.t5_1_1_2_6 hd_h_ml162.t5_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml162.t5_1_1_1_3 hd_h_ml162.t5_1_1_2_7 hd_h_ml162.t5_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml162.t5_1_1_1_3 hd_h_ml162.t5_1_1_2_7 hd_h_ml162.t5_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml162.t5_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NA</td></tr><tr><td headers="hd_h_ml162.t5_1_1_1_1 hd_h_ml162.t5_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">10</td><td headers="hd_h_ml162.t5_1_1_1_1 hd_h_ml162.t5_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2120347</td><td headers="hd_h_ml162.t5_1_1_1_1 hd_h_ml162.t5_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">89856184</td><td headers="hd_h_ml162.t5_1_1_1_1 hd_h_ml162.t5_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-K24426149</td><td headers="hd_h_ml162.t5_1_1_1_1 hd_h_ml162.t5_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml162.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55069/bin/ml162fu26.jpg" alt="Image ml162fu26.jpg" /></div></td><td headers="hd_h_ml162.t5_1_1_1_3 hd_h_ml162.t5_1_1_2_6 hd_h_ml162.t5_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml162.t5_1_1_1_3 hd_h_ml162.t5_1_1_2_6 hd_h_ml162.t5_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml162.t5_1_1_1_3 hd_h_ml162.t5_1_1_2_7 hd_h_ml162.t5_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml162.t5_1_1_1_3 hd_h_ml162.t5_1_1_2_7 hd_h_ml162.t5_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml162.t5_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NA</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>*</dt><dd><div id="ml162.tfn9"><p class="no_margin">P=Purchased; S=Synthesized.</p></div></dd></dl><dl class="bkr_refwrap"><dt></dt><dd><div id="ml162.tfn10"><p class="no_margin">IA=Inactive; ND=Not determined</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobml162t6"><div id="ml162.t6" class="table"><h3><span class="label">Table 6</span><span class="title">Search Strings and Databases Employed in the Prior Art Search</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK55069/table/ml162.t6/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml162.t6_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml162.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Search String</th><th id="hd_h_ml162.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Database</th><th id="hd_h_ml162.t6_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Hits Found</th></tr></thead><tbody><tr><td headers="hd_h_ml162.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">“Ras synthetic lethal”</td><td headers="hd_h_ml162.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Sci Finder</td><td headers="hd_h_ml162.t6_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">52</td></tr><tr><td headers="hd_h_ml162.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">“Ras selective lethal”</td><td headers="hd_h_ml162.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Sci Finder</td><td headers="hd_h_ml162.t6_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">25</td></tr><tr><td headers="hd_h_ml162.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">“Ras synthetic lethal”</td><td headers="hd_h_ml162.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Reaxys</td><td headers="hd_h_ml162.t6_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td></tr><tr><td headers="hd_h_ml162.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">“Ras selective lethal”</td><td headers="hd_h_ml162.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Reaxys</td><td headers="hd_h_ml162.t6_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td></tr><tr><td headers="hd_h_ml162.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">“Ras AND synthetic lethal”</td><td headers="hd_h_ml162.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">USPTO PatFT</td><td headers="hd_h_ml162.t6_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20</td></tr><tr><td headers="hd_h_ml162.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">“Ras AND selective lethal”</td><td headers="hd_h_ml162.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">USPTO PatFT</td><td headers="hd_h_ml162.t6_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td></tr><tr><td headers="hd_h_ml162.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">“Ras AND synthetic lethal”</td><td headers="hd_h_ml162.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">USPTO AppFT</td><td headers="hd_h_ml162.t6_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">56</td></tr><tr><td headers="hd_h_ml162.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">“Ras AND selective lethal”</td><td headers="hd_h_ml162.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">USPTO AppFT</td><td headers="hd_h_ml162.t6_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td></tr><tr><td headers="hd_h_ml162.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">“Ras synthetic lethal”</td><td headers="hd_h_ml162.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">PubChem Bioassay</td><td headers="hd_h_ml162.t6_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">13</td></tr><tr><td headers="hd_h_ml162.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">“Ras selective lethal”</td><td headers="hd_h_ml162.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">PubChem Bioassay</td><td headers="hd_h_ml162.t6_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">13</td></tr><tr><td headers="hd_h_ml162.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">“Ras synthetic lethal”</td><td headers="hd_h_ml162.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">PubMed</td><td headers="hd_h_ml162.t6_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">40</td></tr><tr><td headers="hd_h_ml162.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">“Ras selective lethal”</td><td headers="hd_h_ml162.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">PubMed</td><td headers="hd_h_ml162.t6_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">17</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobml162t7"><div id="ml162.t7" class="table"><h3><span class="label">Table A1</span><span class="title">Summary of Completed Assays and AIDs</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK55069/table/ml162.t7/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml162.t7_lrgtbl__"><table class="no_margin"><thead><tr><th id="hd_h_ml162.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">PubChem AID No.</th><th id="hd_h_ml162.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Type</th><th id="hd_h_ml162.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Target</th><th id="hd_h_ml162.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Concentration Range</th><th id="hd_h_ml162.t7_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Samples Tested</th></tr></thead><tbody><tr><td headers="hd_h_ml162.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1674" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1674</a></td><td headers="hd_h_ml162.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Summary</td><td headers="hd_h_ml162.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NA</td><td headers="hd_h_ml162.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NA</td><td headers="hd_h_ml162.t7_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NA</td></tr><tr><td headers="hd_h_ml162.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1554" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1554</a></td><td headers="hd_h_ml162.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Primary</td><td headers="hd_h_ml162.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BJeLR</td><td headers="hd_h_ml162.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">7.5 μM</td><td headers="hd_h_ml162.t7_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">303344</td></tr><tr><td headers="hd_h_ml162.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1936" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1936</a></td><td headers="hd_h_ml162.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">DR in primary</td><td headers="hd_h_ml162.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BJeLR</td><td headers="hd_h_ml162.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">15 μM – 0.12 μM</td><td headers="hd_h_ml162.t7_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1155</td></tr><tr><td headers="hd_h_ml162.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1935" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1935</a></td><td headers="hd_h_ml162.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Counterscreen</td><td headers="hd_h_ml162.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BJeH-LT</td><td headers="hd_h_ml162.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">15μM – 0.12 μM</td><td headers="hd_h_ml162.t7_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1155</td></tr><tr><td headers="hd_h_ml162.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1934" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1934</a></td><td headers="hd_h_ml162.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Secondary</td><td headers="hd_h_ml162.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">DRD</td><td headers="hd_h_ml162.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">15 μM – 0.12 μM</td><td headers="hd_h_ml162.t7_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1155</td></tr><tr><td headers="hd_h_ml162.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1933" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1933</a></td><td headers="hd_h_ml162.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Counterscreen</td><td headers="hd_h_ml162.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BJeH</td><td headers="hd_h_ml162.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">15 μM – 0.12 μM</td><td headers="hd_h_ml162.t7_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1155</td></tr><tr><td headers="hd_h_ml162.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2610" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2610</a></td><td headers="hd_h_ml162.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Secondary</td><td headers="hd_h_ml162.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BJeLR</td><td headers="hd_h_ml162.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">13.3 μM – 0.10 μM<sup>*</sup></td><td headers="hd_h_ml162.t7_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">435</td></tr><tr><td headers="hd_h_ml162.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2631" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2631</a></td><td headers="hd_h_ml162.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Secondary</td><td headers="hd_h_ml162.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BJeH-LT</td><td headers="hd_h_ml162.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">13.3 μM – 0.10 μM<sup>*</sup></td><td headers="hd_h_ml162.t7_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">435</td></tr><tr><td headers="hd_h_ml162.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2633" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2633</a></td><td headers="hd_h_ml162.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Secondary</td><td headers="hd_h_ml162.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">DRD</td><td headers="hd_h_ml162.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6.7 μM – 0.013 μM<sup>*</sup></td><td headers="hd_h_ml162.t7_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">73</td></tr><tr><td headers="hd_h_ml162.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2635" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2635</a></td><td headers="hd_h_ml162.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Secondary</td><td headers="hd_h_ml162.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BJeH</td><td headers="hd_h_ml162.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6.7 μM – 0.013 μM<sup>*</sup></td><td headers="hd_h_ml162.t7_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">73</td></tr><tr><td headers="hd_h_ml162.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2608" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2608</a></td><td headers="hd_h_ml162.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Secondary- powder</td><td headers="hd_h_ml162.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BJeLR</td><td headers="hd_h_ml162.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20 μM – 20 nM</td><td headers="hd_h_ml162.t7_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">14</td></tr><tr><td headers="hd_h_ml162.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2609" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2609</a></td><td headers="hd_h_ml162.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Secondary- powder</td><td headers="hd_h_ml162.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BJeH-LT</td><td headers="hd_h_ml162.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20 μM – 20 nM</td><td headers="hd_h_ml162.t7_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">14</td></tr><tr><td headers="hd_h_ml162.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2607" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2607</a></td><td headers="hd_h_ml162.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Secondary- powder</td><td headers="hd_h_ml162.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">DRD</td><td headers="hd_h_ml162.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20 μM – 20 nM</td><td headers="hd_h_ml162.t7_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">14</td></tr><tr><td headers="hd_h_ml162.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2611" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2611</a></td><td headers="hd_h_ml162.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Secondary- powder</td><td headers="hd_h_ml162.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BJeH</td><td headers="hd_h_ml162.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20 μM – 20 nM</td><td headers="hd_h_ml162.t7_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">14</td></tr><tr><td headers="hd_h_ml162.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/493045" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">493045</a></td><td headers="hd_h_ml162.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Secondary- powder</td><td headers="hd_h_ml162.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BJeLR</td><td headers="hd_h_ml162.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">45 μM – 45 nM</td><td headers="hd_h_ml162.t7_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20</td></tr><tr><td headers="hd_h_ml162.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/493052" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">493052</a></td><td headers="hd_h_ml162.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Secondary- powder</td><td headers="hd_h_ml162.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BJeH-LT</td><td headers="hd_h_ml162.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">45 μM – 45 nM</td><td headers="hd_h_ml162.t7_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20</td></tr><tr><td headers="hd_h_ml162.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/493049" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">493049</a></td><td headers="hd_h_ml162.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Secondary- powder</td><td headers="hd_h_ml162.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">DRD</td><td headers="hd_h_ml162.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">45 μM – 45 nM</td><td headers="hd_h_ml162.t7_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20</td></tr><tr><td headers="hd_h_ml162.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/493054" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">493054</a></td><td headers="hd_h_ml162.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Secondary- powder</td><td headers="hd_h_ml162.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BJeH</td><td headers="hd_h_ml162.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">45 μM – 45 nM</td><td headers="hd_h_ml162.t7_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>*</dt><dd><div id="ml162.tfn11"><p class="no_margin">Select superactive compounds were retested at a range of 210 nM – 0.41 nM (32X lower)</p></div></dd></dl></dl></div></div></div></article><article data-type="fig" id="figobml162fu2"><div id="ml162.fu2" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162fu27.jpg" alt="1H NMR Spectrum of the probe (CID 3689413/ML162)." /></div><h3><span class="title"><sup>1</sup>H NMR Spectrum of the probe (CID 3689413/<a href="/pcsubstance/?term=ML162[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML162</a>)</span></h3></div></article><article data-type="fig" id="figobml162fu3"><div id="ml162.fu3" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162fu28.jpg" alt="13C NMR Spectrum of the Probe (CID 3689413/ML162)." /></div><h3><span class="title"><sup>13</sup>C NMR Spectrum of the Probe (CID 3689413/<a href="/pcsubstance/?term=ML162[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML162</a>)</span></h3></div></article><article data-type="fig" id="figobml162fu4"><div id="ml162.fu4" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162fu29.jpg" alt="HPLC/MS Chromatogram of the Probe (CID 3689413/ML162) showing >95% purity." /></div><h3><span class="title">HPLC/MS Chromatogram of the Probe (CID 3689413/<a href="/pcsubstance/?term=ML162[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML162</a>) showing >95% purity</span></h3></div></article><article data-type="fig" id="figobml162fu5"><div id="ml162.fu5" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162fu30.jpg" alt="1HNMR Spectra (300 MHz, CDCl3) of Analog CID 46897912." /></div><h3><span class="title"><sup>1</sup>HNMR Spectra (300 MHz, CDCl<sub>3</sub>) of Analog CID 46897912</span></h3></div></article><article data-type="fig" id="figobml162fu6"><div id="ml162.fu6" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162fu31.jpg" alt="UPLC Chromatogram of Analog CID 46897912." /></div><h3><span class="title">UPLC Chromatogram of Analog CID 46897912</span></h3></div></article><article data-type="fig" id="figobml162fu7"><div id="ml162.fu7" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162fu32.jpg" alt="1HNMR Spectra (300 MHz, CDCl3) of Analog CID 46897909." /></div><h3><span class="title"><sup>1</sup>HNMR Spectra (300 MHz, CDCl<sub>3</sub>) of Analog CID 46897909</span></h3></div></article><article data-type="fig" id="figobml162fu8"><div id="ml162.fu8" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162fu33.jpg" alt="UPLC Chromatogram of Analog CID 46897909." /></div><h3><span class="title">UPLC Chromatogram of Analog CID 46897909</span></h3></div></article><article data-type="fig" id="figobml162fu9"><div id="ml162.fu9" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162fu34.jpg" alt="1HNMR Spectra (300 MHz, CDCl3) of Analog CID 46897907." /></div><h3><span class="title"><sup>1</sup>HNMR Spectra (300 MHz, CDCl<sub>3</sub>) of Analog CID 46897907</span></h3></div></article><article data-type="fig" id="figobml162fu10"><div id="ml162.fu10" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162fu35.jpg" alt="UPLC Chromatogram of Analog CID 46897907." /></div><h3><span class="title">UPLC Chromatogram of Analog CID 46897907</span></h3></div></article><article data-type="fig" id="figobml162fu11"><div id="ml162.fu11" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162fu36.jpg" alt="1HNMR Spectra (300 MHz, CDCl3) of Analog CID 49766533." /></div><h3><span class="title"><sup>1</sup>HNMR Spectra (300 MHz, CDCl<sub>3</sub>) of Analog CID 49766533</span></h3></div></article><article data-type="fig" id="figobml162fu12"><div id="ml162.fu12" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162fu37.jpg" alt="UPLC Chromatogram of Analog CID 49766533." /></div><h3><span class="title">UPLC Chromatogram of Analog CID 49766533</span></h3></div></article><article data-type="fig" id="figobml162fu13"><div id="ml162.fu13" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162fu38.jpg" alt="1HNMR Spectra (300 MHz, CDCl3) of Analog CID 3689416." /></div><h3><span class="title"><sup>1</sup>HNMR Spectra (300 MHz, CDCl<sub>3</sub>) of Analog CID 3689416</span></h3></div></article><article data-type="fig" id="figobml162fu14"><div id="ml162.fu14" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162fu39.jpg" alt="UPLC Chromatogram of Analog CID 3689416." /></div><h3><span class="title">UPLC Chromatogram of Analog CID 3689416</span></h3></div></article><article data-type="fig" id="figobml162fu15"><div id="ml162.fu15" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162fu40.jpg" alt="1HNMR Spectra (300 MHz, CDCl3) of Analog CID 3689415." /></div><h3><span class="title"><sup>1</sup>HNMR Spectra (300 MHz, CDCl<sub>3</sub>) of Analog CID 3689415</span></h3></div></article><article data-type="fig" id="figobml162fu16"><div id="ml162.fu16" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162fu41.jpg" alt="UPLC Chromatogram of Analog CID 3689415." /></div><h3><span class="title">UPLC Chromatogram of Analog CID 3689415</span></h3></div></article><article data-type="fig" id="figobml162fu17"><div id="ml162.fu17" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162fu42.jpg" alt="1HNMR Spectra (300 MHz, CDCl3) of Analog CID 3689414." /></div><h3><span class="title"><sup>1</sup>HNMR Spectra (300 MHz, CDCl<sub>3</sub>) of Analog CID 3689414</span></h3></div></article><article data-type="fig" id="figobml162fu18"><div id="ml162.fu18" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162fu43.jpg" alt="UPLC Chromatogram of Analog CID 3689414." /></div><h3><span class="title">UPLC Chromatogram of Analog CID 3689414</span></h3></div></article><article data-type="fig" id="figobml162fu19"><div id="ml162.fu19" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162fu44.jpg" alt="1HNMR (300 MHz, CDCl3) of Analog CID 46897904." /></div><h3><span class="title"><sup>1</sup>HNMR (300 MHz, CDCl<sub>3</sub>) of Analog CID 46897904</span></h3></div></article><article data-type="fig" id="figobml162fu20"><div id="ml162.fu20" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162fu45.jpg" alt="UPLC Chromatogram of Analog CID 46897904." /></div><h3><span class="title">UPLC Chromatogram of Analog CID 46897904</span></h3></div></article><article data-type="fig" id="figobml162fu21"><div id="ml162.fu21" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162fu46.jpg" alt="1HNMR Spectra (300 MHz, CDCl3) of Analog CID 49766510." /></div><h3><span class="title"><sup>1</sup>HNMR Spectra (300 MHz, CDCl<sub>3</sub>) of Analog CID 49766510</span></h3></div></article><article data-type="fig" id="figobml162fu22"><div id="ml162.fu22" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162fu47.jpg" alt="UPLC Chromatogram of Analog CID 49766510." /></div><h3><span class="title">UPLC Chromatogram of Analog CID 49766510</span></h3></div></article><article data-type="fig" id="figobml162fu23"><div id="ml162.fu23" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162fu48.jpg" alt="1HNMR Spectra (300 MHz, CDCl3) of Analog CID 49766537." /></div><h3><span class="title"><sup>1</sup>HNMR Spectra (300 MHz, CDCl<sub>3</sub>) of Analog CID 49766537</span></h3></div></article><article data-type="fig" id="figobml162fu24"><div id="ml162.fu24" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162fu49.jpg" alt="UPLC Chromatogram of Analog CID 49766537." /></div><h3><span class="title">UPLC Chromatogram of Analog CID 49766537</span></h3></div></article><article data-type="fig" id="figobml162fu25"><div id="ml162.fu25" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162fu50.jpg" alt="1HNMR Spectra (300 MHz, CDCl3) of Analog CID 49766511." /></div><h3><span class="title"><sup>1</sup>HNMR Spectra (300 MHz, CDCl<sub>3</sub>) of Analog CID 49766511</span></h3></div></article><article data-type="fig" id="figobml162fu26"><div id="ml162.fu26" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162fu51.jpg" alt="UPLC Chromatogram of Analog CID 49766511." /></div><h3><span class="title">UPLC Chromatogram of Analog CID 49766511</span></h3></div></article><article data-type="fig" id="figobml162fu27"><div id="ml162.fu27" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162fu52.jpg" alt="1HNMR Spectra (300 MHz, CDCl3) of Analog CID 49766514." /></div><h3><span class="title"><sup>1</sup>HNMR Spectra (300 MHz, CDCl<sub>3</sub>) of Analog CID 49766514</span></h3></div></article><article data-type="fig" id="figobml162fu28"><div id="ml162.fu28" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162fu53.jpg" alt="UPLC Chromatogram of Analog CID 49766514." /></div><h3><span class="title">UPLC Chromatogram of Analog CID 49766514</span></h3></div></article><article data-type="fig" id="figobml162fu29"><div id="ml162.fu29" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162fu54.jpg" alt="1HNMR Spectra (300 MHz, CDCl3) of Analog CID 49766515." /></div><h3><span class="title"><sup>1</sup>HNMR Spectra (300 MHz, CDCl<sub>3</sub>) of Analog CID 49766515</span></h3></div></article><article data-type="fig" id="figobml162fu30"><div id="ml162.fu30" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162fu55.jpg" alt="UPLC Chromatogram of Analog CID 49766515." /></div><h3><span class="title">UPLC Chromatogram of Analog CID 49766515</span></h3></div></article><article data-type="fig" id="figobml162fu31"><div id="ml162.fu31" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162fu56.jpg" alt="1HNMR Spectra (300 MHz, CDCl3) of Analog CID 5062094." /></div><h3><span class="title"><sup>1</sup>HNMR Spectra (300 MHz, CDCl<sub>3</sub>) of Analog CID 5062094</span></h3></div></article><article data-type="fig" id="figobml162fu32"><div id="ml162.fu32" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162fu57.jpg" alt="UPLC Chromatogram of Analog CID 5062094." /></div><h3><span class="title">UPLC Chromatogram of Analog CID 5062094</span></h3></div></article><article data-type="fig" id="figobml162fu33"><div id="ml162.fu33" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162fu58.jpg" alt="1HNMR Spectra (300 MHz, CDCl3) of Analog CID 49766544." /></div><h3><span class="title"><sup>1</sup>HNMR Spectra (300 MHz, CDCl<sub>3</sub>) of Analog CID 49766544</span></h3></div></article><article data-type="fig" id="figobml162fu34"><div id="ml162.fu34" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162fu59.jpg" alt="UPLC Chromatogram of Analog CID 49766544." /></div><h3><span class="title">UPLC Chromatogram of Analog CID 49766544</span></h3></div></article><article data-type="fig" id="figobml162fu35"><div id="ml162.fu35" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162fu60.jpg" alt="1HNMR Spectra (300 MHz, CDCl3) of Analog CID 49766532." /></div><h3><span class="title"><sup>1</sup>HNMR Spectra (300 MHz, CDCl<sub>3</sub>) of Analog CID 49766532</span></h3></div></article><article data-type="fig" id="figobml162fu36"><div id="ml162.fu36" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162fu61.jpg" alt="UPLC Chromatogram of Analog CID 49766532." /></div><h3><span class="title">UPLC Chromatogram of Analog CID 49766532</span></h3></div></article><article data-type="fig" id="figobml162fu37"><div id="ml162.fu37" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162fu62.jpg" alt="1HNMR Spectra (300 MHz, CDCl3) of Analog CID 49766508." /></div><h3><span class="title"><sup>1</sup>HNMR Spectra (300 MHz, CDCl<sub>3</sub>) of Analog CID 49766508</span></h3></div></article><article data-type="fig" id="figobml162fu38"><div id="ml162.fu38" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162fu63.jpg" alt="UPLC Chromatogram of Analog CID 49766508." /></div><h3><span class="title">UPLC Chromatogram of Analog CID 49766508</span></h3></div></article><article data-type="fig" id="figobml162fu39"><div id="ml162.fu39" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162fu64.jpg" alt="1HNMR Spectra (300 MHz, CDCl3) of Analog CID 46897910." /></div><h3><span class="title"><sup>1</sup>HNMR Spectra (300 MHz, CDCl<sub>3</sub>) of Analog CID 46897910</span></h3></div></article><article data-type="fig" id="figobml162fu40"><div id="ml162.fu40" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162fu65.jpg" alt="UPLC Chromatogram of Analog CID 46897910." /></div><h3><span class="title">UPLC Chromatogram of Analog CID 46897910</span></h3></div></article><article data-type="fig" id="figobml162fu41"><div id="ml162.fu41" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162fu66.jpg" alt="1HNMR Spectra (300 MHz, CDCl3) of Analog CID 4381125." /></div><h3><span class="title"><sup>1</sup>HNMR Spectra (300 MHz, CDCl<sub>3</sub>) of Analog CID 4381125</span></h3></div></article><article data-type="fig" id="figobml162fu42"><div id="ml162.fu42" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162fu67.jpg" alt="UPLC Chromatogram of Analog CID 4381125." /></div><h3><span class="title">UPLC Chromatogram of Analog CID 4381125</span></h3></div></article><article data-type="fig" id="figobml162fu43"><div id="ml162.fu43" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162fu68.jpg" alt="1HNMR (300 MHz, CDCl3) of Analog CID 2449454." /></div><h3><span class="title"><sup>1</sup>HNMR (300 MHz, CDCl<sub>3</sub>) of Analog CID 2449454</span></h3></div></article><article data-type="fig" id="figobml162fu44"><div id="ml162.fu44" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162fu69.jpg" alt="UPLC Chromatogram of Analog CID 2449454." /></div><h3><span class="title">UPLC Chromatogram of Analog CID 2449454</span></h3></div></article><article data-type="fig" id="figobml162fu45"><div id="ml162.fu45" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162fu70.jpg" alt="1HNMR Spectra (300 MHz, CDCl3) of Analog CID 2416356." /></div><h3><span class="title"><sup>1</sup>HNMR Spectra (300 MHz, CDCl<sub>3</sub>) of Analog CID 2416356</span></h3></div></article><article data-type="fig" id="figobml162fu46"><div id="ml162.fu46" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162fu71.jpg" alt="UPLC Chromatogram of Analog CID 2416356." /></div><h3><span class="title">UPLC Chromatogram of Analog CID 2416356</span></h3></div></article><article data-type="fig" id="figobml162fu47"><div id="ml162.fu47" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162fu72.jpg" alt="1HNMR Spectra (300 MHz, CDCl3) of Analog CID 6545175." /></div><h3><span class="title"><sup>1</sup>HNMR Spectra (300 MHz, CDCl<sub>3</sub>) of Analog CID 6545175</span></h3></div></article><article data-type="fig" id="figobml162fu48"><div id="ml162.fu48" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162fu73.jpg" alt="UPLC Chromatogram of Analog CID 6545175." /></div><h3><span class="title">UPLC Chromatogram of Analog CID 6545175</span></h3></div></article><article data-type="fig" id="figobml162fu49"><div id="ml162.fu49" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162fu74.jpg" alt="1HNMR Spectra (300 MHz, CDCl3) of Analog CID 1637653." /></div><h3><span class="title"><sup>1</sup>HNMR Spectra (300 MHz, CDCl<sub>3</sub>) of Analog CID 1637653</span></h3></div></article><article data-type="fig" id="figobml162fu50"><div id="ml162.fu50" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162fu75.jpg" alt="UPLC Chromatogram of Analog CID 1637653." /></div><h3><span class="title">UPLC Chromatogram of Analog CID 1637653</span></h3></div></article><article data-type="fig" id="figobml162fu51"><div id="ml162.fu51" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162fu76.jpg" alt="1HNMR Spectra (300 MHz, CDCl3) of Analog CID 2345373." /></div><h3><span class="title"><sup>1</sup>HNMR Spectra (300 MHz, CDCl<sub>3</sub>) of Analog CID 2345373</span></h3></div></article><article data-type="fig" id="figobml162fu52"><div id="ml162.fu52" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162fu77.jpg" alt="UPLC Chromatogram of Analog CID 2345373." /></div><h3><span class="title">UPLC Chromatogram of Analog CID 2345373</span></h3></div></article><article data-type="fig" id="figobml162fu53"><div id="ml162.fu53" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162fu78.jpg" alt="1HNMR Spectra (300 MHz, CDCl3) of Analog CID 566661." /></div><h3><span class="title"><sup>1</sup>HNMR Spectra (300 MHz, CDCl<sub>3</sub>) of Analog CID 566661</span></h3></div></article><article data-type="fig" id="figobml162fu54"><div id="ml162.fu54" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162fu79.jpg" alt="UPLC Chromatogram of Analog CID 566661." /></div><h3><span class="title">UPLC Chromatogram of Analog CID 566661</span></h3></div></article><article data-type="fig" id="figobml162fu55"><div id="ml162.fu55" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162fu80.jpg" alt="1HNMR Spectra (300 MHz, CDCl3) of Analog CID 2120347." /></div><h3><span class="title"><sup>1</sup>HNMR Spectra (300 MHz, CDCl<sub>3</sub>) of Analog CID 2120347</span></h3></div></article><article data-type="fig" id="figobml162fu56"><div id="ml162.fu56" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55069/bin/ml162fu81.jpg" alt="UPLC Chromatogram of Analog CID 2120347." /></div><h3><span class="title">UPLC Chromatogram of Analog CID 2120347</span></h3></div></article><article data-type="table-wrap" id="figobml162t8"><div id="ml162.t8" class="table"><h3><span class="label">Table A2</span><span class="title">Probe and Analog Information</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK55069/table/ml162.t8/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml162.t8_lrgtbl__"><table class="no_margin"><thead><tr><th id="hd_h_ml162.t8_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">BRD</th><th id="hd_h_ml162.t8_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">SID</th><th id="hd_h_ml162.t8_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CID</th><th id="hd_h_ml162.t8_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">P/A</th><th id="hd_h_ml162.t8_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">MLSID</th><th id="hd_h_ml162.t8_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">ML</th></tr></thead><tbody><tr><td headers="hd_h_ml162.t8_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-A36275421-001-06-1</td><td headers="hd_h_ml162.t8_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/89856179" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">89856179</a></td><td headers="hd_h_ml162.t8_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3689413</td><td headers="hd_h_ml162.t8_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml162.t8_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS002703080</td><td headers="hd_h_ml162.t8_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="/pcsubstance/?term=ML162[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML162</a></td></tr><tr><td headers="hd_h_ml162.t8_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-A39093044-001-05-4</td><td headers="hd_h_ml162.t8_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/89856180" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">89856180</a></td><td headers="hd_h_ml162.t8_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3689415</td><td headers="hd_h_ml162.t8_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">A</td><td headers="hd_h_ml162.t8_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS002703081</td><td headers="hd_h_ml162.t8_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NA</td></tr><tr><td headers="hd_h_ml162.t8_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-A72180425-001-06-4</td><td headers="hd_h_ml162.t8_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/89856181" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">89856181</a></td><td headers="hd_h_ml162.t8_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3689416</td><td headers="hd_h_ml162.t8_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">A</td><td headers="hd_h_ml162.t8_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS002703082</td><td headers="hd_h_ml162.t8_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NA</td></tr><tr><td headers="hd_h_ml162.t8_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-A76490030-001-06-0</td><td headers="hd_h_ml162.t8_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/89856182" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">89856182</a></td><td headers="hd_h_ml162.t8_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4381125</td><td headers="hd_h_ml162.t8_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">A</td><td headers="hd_h_ml162.t8_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS002703079</td><td headers="hd_h_ml162.t8_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NA</td></tr><tr><td headers="hd_h_ml162.t8_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-A76490030-001-06-0</td><td headers="hd_h_ml162.t8_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/89856187" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">89856187</a></td><td headers="hd_h_ml162.t8_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2449454</td><td headers="hd_h_ml162.t8_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">A</td><td headers="hd_h_ml162.t8_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS002703083</td><td headers="hd_h_ml162.t8_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NA</td></tr><tr><td headers="hd_h_ml162.t8_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-K62459624-001-07-9</td><td headers="hd_h_ml162.t8_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/89856188" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">89856188</a></td><td headers="hd_h_ml162.t8_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2416356</td><td headers="hd_h_ml162.t8_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">A</td><td headers="hd_h_ml162.t8_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS002703084</td><td headers="hd_h_ml162.t8_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NA</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div id="ml162.tfn12"><p class="no_margin">P = probe, A = analog</p></div></dd></dl></dl></div></div></div></article></div><div id="jr-scripts"><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/libs.min.js"> </script><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.min.js"> </script></div></div>
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