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<script type="text/javascript" src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.boots.min.js"> </script><title>Small-molecule antagonists of Gli function - 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="Small-molecule antagonists of Gli function">
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<meta name="citation_publisher" content="National Center for Biotechnology Information (US)">
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<meta name="citation_date" content="2014/05/13">
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<meta name="citation_author" content="Robert Ardecky">
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<meta name="citation_author" content="Gavin K. Magnuson">
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<meta name="citation_author" content="Jiwen Zou">
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<meta name="citation_author" content="Santhi R. Ganji">
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<meta name="citation_author" content="Brock Brown">
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<meta name="citation_author" content="Tram Ngo">
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<meta name="citation_author" content="Julia Lee">
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<meta name="citation_author" content="Fu-Yue Zeng">
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<meta name="citation_author" content="Qing Sun">
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<meta name="citation_author" content="Derek Stonich">
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<meta name="citation_author" content="Sumeet Salaniwal">
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<meta name="citation_author" content="Tomoyo Sakata">
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<meta name="citation_author" content="Paul G. Rack">
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<meta name="citation_author" content="Jennifer K. T. Casabar">
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<meta name="citation_author" content="Arianna Mangravita-Novo">
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<meta name="citation_author" content="Layton H. Smith">
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<meta name="citation_author" content="Eduard Sergienko">
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<meta name="citation_author" content="Thomas D.Y. Chung">
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<meta name="citation_author" content="Anthony B. Pinkerton">
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<meta name="citation_author" content="Ian Pass">
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<meta name="citation_author" content="James K. Chen">
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<meta name="DC.Title" content="Small-molecule antagonists of Gli function">
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<meta name="DC.Publisher" content="National Center for Biotechnology Information (US)">
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<meta name="DC.Contributor" content="Robert Ardecky">
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<meta name="DC.Contributor" content="Gavin K. Magnuson">
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<meta name="DC.Contributor" content="Jiwen Zou">
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<meta name="DC.Contributor" content="Santhi R. Ganji">
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<meta name="DC.Contributor" content="Brock Brown">
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<meta name="DC.Contributor" content="Tram Ngo">
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<meta name="DC.Contributor" content="Julia Lee">
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<meta name="DC.Contributor" content="Fu-Yue Zeng">
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<meta name="DC.Contributor" content="Qing Sun">
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<meta name="DC.Contributor" content="Derek Stonich">
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<meta name="DC.Contributor" content="Sumeet Salaniwal">
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<meta name="DC.Contributor" content="Tomoyo Sakata">
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<meta name="DC.Contributor" content="Paul G. Rack">
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<meta name="DC.Contributor" content="Jennifer K. T. Casabar">
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<meta name="DC.Contributor" content="Arianna Mangravita-Novo">
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<meta name="DC.Contributor" content="Layton H. Smith">
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<meta name="DC.Contributor" content="Eduard Sergienko">
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<meta name="DC.Contributor" content="Thomas D.Y. Chung">
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<meta name="DC.Contributor" content="Anthony B. Pinkerton">
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<meta name="DC.Contributor" content="Ian Pass">
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<meta name="DC.Contributor" content="James K. Chen">
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<meta name="DC.Date" content="2014/05/13">
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<meta name="description" content="As cancer treatments have shifted toward targeted therapies, the role of developmental signaling pathways in tumorigenesis has garnered special attention. For example, the Hedgehog (Hh) pathway is required for cerebellar development, and its constitutive activation can lead to pediatric medulloblastomas. Hh signaling is normally initiated by the binding of Hh ligands (Shh, Ihh, and Dhh) to the 12TM Patched1 (Ptch1) receptor resulting in accumulation and activation of the G protein-coupled receptor-like protein Smoothened (Smo) within the primary cilium. How Smo regulates Gli transcription factor function remains unclear, but this process involve the scaffolding protein Suppressor of Fused (Sufu), which can directly inhibit the Gli proteins and facilitate their proteolytic processing into N-terminal repressors. Smo is perhaps the most “druggable” target within the Hh pathway, and Smo inhibitors have demonstrated efficacy in murine tumor models and human clinical trials. However, certain cancers can proliferate in response to Gli activation through noncanonical mechanisms and therefore are insensitive to Smo inhibitors. Tumors that initially respond to Smo antagonists can also acquire mutations in Smo or downstream pathway components that render them resistant to these chemotherapies. Chemical inhibitors that act downstream of Smo therefore constitute an important therapeutic strategy for the treatment of Hh pathway-dependent cancers. Most current approaches are biased overwhelmingly to find Smo antagonists or use non-physiological overexpressed Gli cell systems. We overcame these limitations by employing a cell-based reporter that lacks Sufu (Sufu-KO-LIGHT cells) and exhibits constitutive Hh target gene expression in response to endogenous Gli activators to interrogate the MLSMR. We report here for the first time on a novel potent (33.6 nM IC50), non-cytotoxic small molecule antagonist of Gli function that does not inhibit Wnt3a signaling.">
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<meta name="og:title" content="Small-molecule antagonists of Gli function">
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<meta name="og:description" content="As cancer treatments have shifted toward targeted therapies, the role of developmental signaling pathways in tumorigenesis has garnered special attention. For example, the Hedgehog (Hh) pathway is required for cerebellar development, and its constitutive activation can lead to pediatric medulloblastomas. Hh signaling is normally initiated by the binding of Hh ligands (Shh, Ihh, and Dhh) to the 12TM Patched1 (Ptch1) receptor resulting in accumulation and activation of the G protein-coupled receptor-like protein Smoothened (Smo) within the primary cilium. How Smo regulates Gli transcription factor function remains unclear, but this process involve the scaffolding protein Suppressor of Fused (Sufu), which can directly inhibit the Gli proteins and facilitate their proteolytic processing into N-terminal repressors. Smo is perhaps the most “druggable” target within the Hh pathway, and Smo inhibitors have demonstrated efficacy in murine tumor models and human clinical trials. However, certain cancers can proliferate in response to Gli activation through noncanonical mechanisms and therefore are insensitive to Smo inhibitors. Tumors that initially respond to Smo antagonists can also acquire mutations in Smo or downstream pathway components that render them resistant to these chemotherapies. Chemical inhibitors that act downstream of Smo therefore constitute an important therapeutic strategy for the treatment of Hh pathway-dependent cancers. Most current approaches are biased overwhelmingly to find Smo antagonists or use non-physiological overexpressed Gli cell systems. We overcame these limitations by employing a cell-based reporter that lacks Sufu (Sufu-KO-LIGHT cells) and exhibits constitutive Hh target gene expression in response to endogenous Gli activators to interrogate the MLSMR. We report here for the first time on a novel potent (33.6 nM IC50), non-cytotoxic small molecule antagonist of Gli function that does not inhibit Wnt3a signaling.">
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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="_NBK158949_"><span class="title" itemprop="name">Small-molecule antagonists of Gli function</span></h1><p class="contribs">Ardecky R, Magnuson GK, Zou J, et al.</p><p class="fm-aai"><a href="#_NBK158949_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>As cancer treatments have shifted toward targeted therapies, the role of developmental signaling pathways in tumorigenesis has garnered special attention. For example, the Hedgehog (Hh) pathway is required for cerebellar development, and its constitutive activation can lead to pediatric medulloblastomas. Hh signaling is normally initiated by the binding of Hh ligands (Shh, Ihh, and Dhh) to the 12TM Patched1 (Ptch1) receptor resulting in accumulation and activation of the G protein-coupled receptor-like protein Smoothened (Smo) within the primary cilium. How Smo regulates Gli transcription factor function remains unclear, but this process involve the scaffolding protein Suppressor of Fused (Sufu), which can directly inhibit the Gli proteins and facilitate their proteolytic processing into N-terminal repressors. Smo is perhaps the most “druggable” target within the Hh pathway, and Smo inhibitors have demonstrated efficacy in murine tumor models and human clinical trials. However, certain cancers can proliferate in response to Gli activation through noncanonical mechanisms and therefore are insensitive to Smo inhibitors. Tumors that initially respond to Smo antagonists can also acquire mutations in Smo or downstream pathway components that render them resistant to these chemotherapies. Chemical inhibitors that act downstream of Smo therefore constitute an important therapeutic strategy for the treatment of Hh pathway-dependent cancers. Most current approaches are biased overwhelmingly to find Smo antagonists or use non-physiological overexpressed Gli cell systems. We overcame these limitations by employing a cell-based reporter that lacks Sufu (Sufu-KO-LIGHT cells) and exhibits constitutive Hh target gene expression in response to <i>endogenous</i> Gli activators to interrogate the MLSMR. We report here for the first time on a novel potent (33.6 nM IC<sub>50</sub>), non-cytotoxic small molecule antagonist of Gli function that does not inhibit Wnt3a signaling.</p></div><div class="h2"></div><p><b>Assigned Assay Grant #:</b> 1R03MH094195-01</p><p><b>Screening Center Name & PI:</b> Sanford Burnham Center for Chemical Genomics (SBCCG) & John C. Reed (PI)</p><p><b>Chemistry Center Name & PI:</b> Sanford Burnham Center for Chemical Genomics (SBCCG) & John C. Reed (PI)</p><p><b>Assay Submitter & Institution:</b> James K. Chen, Ph.D., Stanford University, Stanford, CA, USA.</p><p><b>PubChem Summary Bioassay Identifier (AID):</b>
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<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588433" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">588433</a></p><div id="ml340.s1"><h2 id="_ml340_s1_">Probe Structure & Characteristics</h2><p>This Center Probe Report describes a novel chemical scaffold <a href="/pcsubstance/?term=ML340[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML340</a>, which potently blocks Gli-dependent transcription but does not block Wnt signaling.</p><div id="ml340.fu1" class="figure bk_fig"><div class="graphic"><img src="/books/NBK158949/bin/ml340fu1.jpg" alt="ML340." /></div><h3><span class="title">ML340</span></h3></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml340t1"><a href="/books/NBK158949/table/ml340.t1/?report=objectonly" target="object" title="Table 1" class="img_link icnblk_img figpopup" rid-figpopup="figml340t1" rid-ob="figobml340t1"><img class="small-thumb" src="/books/NBK158949/table/ml340.t1/?report=thumb" src-large="/books/NBK158949/table/ml340.t1/?report=previmg" alt="Table 1. Potency and selectivity characteristics for probes ML340." /></a><div class="icnblk_cntnt"><h4 id="ml340.t1"><a href="/books/NBK158949/table/ml340.t1/?report=objectonly" target="object" rid-ob="figobml340t1">Table 1</a></h4><p class="float-caption no_bottom_margin">Potency and selectivity characteristics for probes ML340. </p></div></div></div><div id="ml340.s2"><h2 id="_ml340_s2_">Recommendations for scientific use of the probe</h2><p>Nearly all known Hh pathway inhibitors target the transmembrane protein Smo, and therefore probes that act on downstream signaling proteins are needed. The proposed screen will help identify small molecules that are epistatic to the Gli antagonist Sufu, providing reagents for studying the mechanisms that regulate Gli transcription factor function and structural leads for new Hh pathway-targeting anti-cancer therapies. These compounds will be particularly valuable to the developmental biology and cancer biology communities, as the biochemical and cellular processes that control Gli activity state remain elusive and Hh pathway-dependent tumors that acquire resistance to Smo antagonists have been observed in the clinic.</p></div><div id="ml340.s3"><h2 id="_ml340_s3_">1. Introduction</h2><p>This probe project aimed to generate small molecule inhibitors of Gli transcription factor function and be demonstrate selectivity over other developmental pathways such as Wnt signaling.</p><div id="ml340.s4"><h3>Specific Aims <i>(verbatim from original R03 application)</i></h3><p><b>Specific Aim 1.</b> Screen the NIH Molecular Libraries-Small Molecule Repository (MLSMR) collection for Gli antagonists using the Sufu-KO-LIGHT cell assay described herein.</p><p><b>Specific Aim 2.</b> Perform secondary assays to validate chemical hits (probes).</p><ul class="simple-list"><li class="half_rhythm"><div><b>Subaim 2a:</b> To validate Hh pathway-selective probes using cell lines responsive to Hh ligands or other growth factors.</div></li><li class="half_rhythm"><div><b>Subaim 2b:</b> To investigate how these compounds modulate Gli function, phosphorylation, proteolysis, and trafficking in Hh-responsive cells.</div></li><li class="half_rhythm"><div><b>Subaim 2c:</b> To test validated compounds on cell-based models of Hh pathway-dependent cancers.</div></li></ul></div><div id="ml340.s5"><h3>Background and Significance</h3><p>As cancer treatments have shifted toward targeted therapies, the role of developmental signaling pathways in tumorigenesis has garnered special attention. The molecular links between ontogeny, stem cell biology, and oncogenesis is exemplified by the Hh pathway, which plays a critical role in the patterning of certain embryonic tissues and contributes to their neoplastic transformation later in life. For example, Hh signaling regulates cerebellar patterning by promoting the proliferation of neuronal precursor cells, and constitutive Hh target gene expression can lead to medulloblastoma, the most common pediatric brain tumor[<a class="bibr" href="#ml340.r1" rid="ml340.r1">1</a>].</p><p>Hh signaling is normally initiated by the binding of Hh ligands—Sonic, Indian, and Desert Hh (Shh, Ihh, and Dhh) in mammals—to the twelve-pass transmembrane protein Patched1 (Ptch1), which is localized to a microtubule-based protrusion in the plasma membrane called the primary cilium (<a class="figpopup" href="/books/NBK158949/figure/ml340.f1/?report=objectonly" target="object" rid-figpopup="figml340f1" rid-ob="figobml340f1">Figure 1</a>)[<a class="bibr" href="#ml340.r2" rid="ml340.r2">2</a>]. Ligand binding induces Ptch1 exit from the cilium, leading to Smo accumulation and activation within this antenna-like organelle. Activated Smo then shifts the balance between repressor and activator forms of the Gli transcription factors (Gli1, Gli2, and Gli3). While Gli2 and Gli3 are normally proteolytically processed into N-terminal repressors (Gli2/3R) in a primary cilium-, phosphorylation-, and proteosome-dependent manner, Smo promotes the stabilization of full-length Gli proteins, their conversion into transcriptional activators (Gli2/3A), and their accumulation at the distal tip of the cilium. How Smo regulates Gli function remains unclear, but this process appears to involve the scaffolding protein Suppressor of Fused (Sufu), which can directly inhibit the Gli proteins and facilitate their proteolysis. The activator form of Gli2, and to a lesser extent that of Gli3, subsequently drives the expression of Hh target genes, including cell cycle regulators, oncogenes, <i>Ptch1</i>, and the constitutively active transcription factor <i>Gli1</i>. Oncogenic Hh pathway activation can be initiated at multiple points within the signaling mechanism described previously. Mouse models suggest that prostate cancer can require Hh ligand-dependent paracrine signaling for its proliferation[<a class="bibr" href="#ml340.r3" rid="ml340.r3">3</a>], whereas small cell lung cancer is believed to involve autocrine pathway activation[<a class="bibr" href="#ml340.r4" rid="ml340.r4">4</a>]. Ligand-independent Hh target gene expression is operative in other cases. Nearly all basal cell carcinomas contain inactivating mutations in <i>Ptch1</i> or activating mutations in <i>Smo</i>[<a class="bibr" href="#ml340.r5" rid="ml340.r5">5</a>–<a class="bibr" href="#ml340.r7" rid="ml340.r7">7</a>], and medulloblastomas can be caused by mutations in these transmembrane proteins[<a class="bibr" href="#ml340.r8" rid="ml340.r8">8</a>–<a class="bibr" href="#ml340.r10" rid="ml340.r10">10</a>] or the downstream regulator <i>Sufu</i>[<a class="bibr" href="#ml340.r11" rid="ml340.r11">11</a>]. These observations have prompted the development of Hh pathway inhibitors by several academic and industrial laboratories, resulting in a large ensemble of Smo antagonists[<a class="bibr" href="#ml340.r12" rid="ml340.r12">12</a>]. As a GPCR-like signaling protein, Smo is perhaps the most “druggable” target within the Hh pathway, and Smo inhibitors have demonstrated efficacy in murine tumor models[<a class="bibr" href="#ml340.r13" rid="ml340.r13">13</a>–<a class="bibr" href="#ml340.r19" rid="ml340.r19">19</a>] and human clinical trials[<a class="bibr" href="#ml340.r20" rid="ml340.r20">20</a>,<a class="bibr" href="#ml340.r21" rid="ml340.r21">21</a>]. For example, Genentech reported last year that the Smo antagonist GDC-0449 induced significant tumor regressions in patients with either metastatic basal cell carcinoma or medulloblastoma[<a class="bibr" href="#ml340.r20" rid="ml340.r20">20</a>,<a class="bibr" href="#ml340.r21" rid="ml340.r21">21</a>]. Yet the excitement generated by these findings is tempered by the emergence of GDC-0449-resistant tumors, which either contain point mutations in Smo that prevent drug binding or sustain Hh target gene expression in a Smo-independent manner[<a class="bibr" href="#ml340.r21" rid="ml340.r21">21</a>]. Tumors expressing GDC-0449-resistant Smo were also insensitive to cyclopamine, a structurally distinct Smo inhibitor[<a class="bibr" href="#ml340.r22" rid="ml340.r22">22</a>], suggesting that the development of additional Smo antagonists will not be an adequate solution to this problem. Moreover, certain cancers such as Ewing’s sarcoma and KRAS-induced pancreatic adenocarcinoma can proliferate in response to Gli activation through noncanonical mechanisms[<a class="bibr" href="#ml340.r23" rid="ml340.r23">23</a>–<a class="bibr" href="#ml340.r27" rid="ml340.r27">27</a>], and Smo inhibitors will be ineffective against these diseases.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml340f1" co-legend-rid="figlgndml340f1"><a href="/books/NBK158949/figure/ml340.f1/?report=objectonly" target="object" title="Fig. 1" class="img_link icnblk_img figpopup" rid-figpopup="figml340f1" rid-ob="figobml340f1"><img class="small-thumb" src="/books/NBK158949/bin/ml340f1.gif" src-large="/books/NBK158949/bin/ml340f1.jpg" alt="Fig. 1. The Hh pathway." /></a><div class="icnblk_cntnt" id="figlgndml340f1"><h4 id="ml340.f1"><a href="/books/NBK158949/figure/ml340.f1/?report=objectonly" target="object" rid-ob="figobml340f1">Fig. 1</a></h4><p class="float-caption no_bottom_margin">The Hh pathway. Functional interactions between Hh signaling components and representative small-molecule inhibitors of the pathway are shown. Positive and negative regulatory proteins are depicted in green and red. respectively. </p></div></div><p>Chemical inhibitors that act downstream of Smo therefore constitute an important therapeutic strategy for the treatment of Hh pathway-dependent cancers. Unfortunately discovering such small molecules is not a trivial endeavor. Due to the high susceptibility of Smo to small-molecule modulation, high-throughput screens using Hh ligand-stimulated cells are overwhelmingly dominated by Smo antagonists[<a class="bibr" href="#ml340.r28" rid="ml340.r28">28</a>]. Our laboratory also recently screened 120,000 compounds for their ability to inhibit Hh target gene expression induced by saturating amounts of a chemical Smo agonist, yielding four antagonists of Gli function (HPI-1 through 4)[<a class="bibr" href="#ml340.r29" rid="ml340.r29">29</a>]. Yet even these conditions failed to exclude hundreds of Smo inhibitors, requiring extensive, time-consuming secondary assays to identify and segregate these upstream-acting antagonists. Alternative approaches by other laboratories have utilized cells stably transfected for Gli1 or Gli2 overexpression[<a class="bibr" href="#ml340.r30" rid="ml340.r30">30</a>–<a class="bibr" href="#ml340.r32" rid="ml340.r32">32</a>]; however, these assay conditions survey only a limited range of “druggable” Gli regulatory mechanisms, as overexpressed Gli transcription factors escape several of the biochemical and cellular processes that control Gli function. The research plan described in this application overcomes these limitations by employing a cell-based reporter that lacks Sufu and exhibits constitutive Hh target gene expression in response to endogenous Gli activators. We emphasize that previous studies all screened using Gli-overexpressing cells, which favors hit compounds that target a subset of Gli regulatory mechanisms (since overexpressed Gli escapes certain regulatory processes. In contrast, the Sufu-KO-LIGHT cells used for this project rely on endogenous Gli for their activity. The project screen is therefore configured to identify antagonists that would have been missed in earlier studies.</p></div><div id="ml340.s6"><h3>Prior Art</h3><p>The Hedgehog (Hh) signaling pathway is a key regulator of embryonic development and stem cell self-renewal, and its inappropriate activation can promote the onset and/or progression of several human cancers[<a class="bibr" href="#ml340.r1" rid="ml340.r1">1</a>]. In particular, Hh pathway dysregulation has been linked to tumors of the brain, skin, pancreas, breast, ovaries, and blood, and small molecules targeting this pathway are now being pursued as anti-cancer therapies[<a class="bibr" href="#ml340.r12" rid="ml340.r12">12</a>,<a class="bibr" href="#ml340.r33" rid="ml340.r33">33</a>]. However, the vast majority of these compounds inhibit Smoothened (Smo), a G protein-coupled receptor-like transducer of the Hh signal, and some antagonists have already been tested in human clinical trials[<a class="bibr" href="#ml340.r20" rid="ml340.r20">20</a>,<a class="bibr" href="#ml340.r21" rid="ml340.r21">21</a>,<a class="bibr" href="#ml340.r33" rid="ml340.r33">33</a>]. Small-molecule screens that have focused on downstream signaling events have utilized Gli-overexpressing cells, which favors hit compounds that target a subset of Gli regulatory mechanisms (since overexpressed Gli escapes certain regulatory processes. In contrast, the Sufu-KO-LIGHT cells used for this project rely on endogenous Gli for their activity. The project screen is therefore configured to identify antagonists that would have been missed in earlier studies.</p><p>During our validation and optimization of the Sufu-KO-LIGHT assay, as expected, GDC-0449 was unable to reduce firefly luciferase levels in these cells even though it inhibits Smo activity with nanomolar potency[<a class="bibr" href="#ml340.r17" rid="ml340.r17">17</a>], whereas HPI-1 blocks reporter expression in a dose-dependent manner (IC50 = 0.90 μM; Hill coefficient ~1) - <i>see</i>
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<a class="figpopup" href="/books/NBK158949/figure/ml340.f2/?report=objectonly" target="object" rid-figpopup="figml340f2" rid-ob="figobml340f2">Figure 2</a></p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml340f2" co-legend-rid="figlgndml340f2"><a href="/books/NBK158949/figure/ml340.f2/?report=objectonly" target="object" title="Figure 2" class="img_link icnblk_img figpopup" rid-figpopup="figml340f2" rid-ob="figobml340f2"><img class="small-thumb" src="/books/NBK158949/bin/ml340f2.gif" src-large="/books/NBK158949/bin/ml340f2.jpg" alt="Figure 2. Inhibition of Gli-Sufu-KO LIGHT reporter by HPI-1 and GDC-0449." /></a><div class="icnblk_cntnt" id="figlgndml340f2"><h4 id="ml340.f2"><a href="/books/NBK158949/figure/ml340.f2/?report=objectonly" target="object" rid-ob="figobml340f2">Figure 2</a></h4><p class="float-caption no_bottom_margin">Inhibition of Gli-Sufu-KO LIGHT reporter by HPI-1 and GDC-0449. </p></div></div><p>A SciFinder search for Gli antagonists found several of the citations in this introduction describing Smo inhibitors[<a class="bibr" href="#ml340.r12" rid="ml340.r12">12</a>,<a class="bibr" href="#ml340.r29" rid="ml340.r29">29</a>–<a class="bibr" href="#ml340.r32" rid="ml340.r32">32</a>]. Moreover, while several citations describe Gli antagonists[<a class="bibr" href="#ml340.r34" rid="ml340.r34">34</a>–<a class="bibr" href="#ml340.r38" rid="ml340.r38">38</a>], these antagonists have been found using cell assays with <i>overexpressed</i> Gli, which suffers from escape of certain Gli regulatory processes, as noted previously. Also the follow-on work to establish the Gli pathway antagonism in these publications is incomplete and inconclusive.</p></div></div><div id="ml340.s7"><h2 id="_ml340_s7_">2. Materials and Methods</h2><p>The key reagent that enables this project is the Sufu-KO-LIGHT cell line provided by Prof. Chen, containing cell-based reporter that lacks Sufu and exhibits constitutive Hh target gene expression in response to endogenous Gli activators. Previous studies all screened using Gli-overexpressing cells[<a class="bibr" href="#ml340.r30" rid="ml340.r30">30</a>–<a class="bibr" href="#ml340.r32" rid="ml340.r32">32</a>] which favors hit compounds that target a subset of Gli regulatory mechanisms (since overexpressed Gli escapes certain regulatory processes). The details of the primary HTS and additional assays can be found in the “Assay Description” section in the PubChem BioAssay view under the AIDs as listed in <a class="figpopup" href="/books/NBK158949/table/ml340.t2/?report=objectonly" target="object" rid-figpopup="figml340t2" rid-ob="figobml340t2">Table 2</a>. Additionally the details for the primary HTS are provided in the Appendix at the end of this probe report.</p><div id="ml340.s8"><h3>2.1. Assays</h3><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml340t2"><a href="/books/NBK158949/table/ml340.t2/?report=objectonly" target="object" title="Table 2" class="img_link icnblk_img figpopup" rid-figpopup="figml340t2" rid-ob="figobml340t2"><img class="small-thumb" src="/books/NBK158949/table/ml340.t2/?report=thumb" src-large="/books/NBK158949/table/ml340.t2/?report=previmg" alt="Table 2. Summary of Assays and AIDs." /></a><div class="icnblk_cntnt"><h4 id="ml340.t2"><a href="/books/NBK158949/table/ml340.t2/?report=objectonly" target="object" rid-ob="figobml340t2">Table 2</a></h4><p class="float-caption no_bottom_margin">Summary of Assays and AIDs. </p></div></div></div><div id="ml340.s9"><h3>2.2. Probe Chemical Characterization</h3><div id="ml340.s10"><h4>a. Chemical name of probe compound <i>[IUPAC name must match PubChem]</i></h4><p>The IUPAC name of the probe [<a href="/pcsubstance/?term=ML340[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML340</a><b>]</b> is N-(6-(4-methylpiperidin-1-yl)pyrimidin-4-yl)benzamide (<i>PubChem currently does not have an IUPAC name</i>). The actual batch prepared, tested and submitted to the MLSMR is <a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864401" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 150864401</a> corresponding to CID 65389180.</p></div><div id="ml340.s11"><h4>b. Probe chemical structure including stereochemistry if known</h4><p>Probe <a href="/pcsubstance/?term=ML340[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML340</a> does not contain any stereocenters (see <a class="figpopup" href="/books/NBK158949/figure/ml340.f3/?report=objectonly" target="object" rid-figpopup="figml340f3" rid-ob="figobml340f3">Figure 3</a>)</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml340f3" co-legend-rid="figlgndml340f3"><a href="/books/NBK158949/figure/ml340.f3/?report=objectonly" target="object" title="Figure 3" class="img_link icnblk_img figpopup" rid-figpopup="figml340f3" rid-ob="figobml340f3"><img class="small-thumb" src="/books/NBK158949/bin/ml340f3.gif" src-large="/books/NBK158949/bin/ml340f3.jpg" alt="Figure 3. Structure of ML340." /></a><div class="icnblk_cntnt" id="figlgndml340f3"><h4 id="ml340.f3"><a href="/books/NBK158949/figure/ml340.f3/?report=objectonly" target="object" rid-ob="figobml340f3">Figure 3</a></h4><p class="float-caption no_bottom_margin">Structure of <i>ML340</i>. </p></div></div></div><div id="ml340.s12"><h4>c. Structural Verification I<i>nformation of probe SID</i> 150864401 <i>corresp</i>onding to CID 6538918 (ML340)</h4><p>For detailed synthetic procedures and structural verification see <a href="#ml340.s17">Section 2.3</a>. The spectral data (<sup>1</sup>HNMR, <sup>13</sup>CNMR, and HPLC/MS) used to support the structural assignment of <a href="/pcsubstance/?term=ML340[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML340</a> can be found in <a href="#ml340.s30">Section 6 (Supplementary Information)</a>.</p></div><div id="ml340.s13"><h4>d. If available from a vendor, please provide details</h4><p>The probe is not commercially available. We synthesized this compound and deposited 34 mg with MLSMR (Bio-Focus DPI), (see probe Submission <a class="figpopup" href="/books/NBK158949/table/ml340.t4/?report=objectonly" target="object" rid-figpopup="figml340t4" rid-ob="figobml340t4">Table 4</a>)</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml340t4"><a href="/books/NBK158949/table/ml340.t4/?report=objectonly" target="object" title="Table 4" class="img_link icnblk_img figpopup" rid-figpopup="figml340t4" rid-ob="figobml340t4"><img class="small-thumb" src="/books/NBK158949/table/ml340.t4/?report=thumb" src-large="/books/NBK158949/table/ml340.t4/?report=previmg" alt="Table 4. Probe and Analog Submissions to MLSMR (BioFocus DPI) for Gli-Sufu Antagonist ML340." /></a><div class="icnblk_cntnt"><h4 id="ml340.t4"><a href="/books/NBK158949/table/ml340.t4/?report=objectonly" target="object" rid-ob="figobml340t4">Table 4</a></h4><p class="float-caption no_bottom_margin">Probe and Analog Submissions to MLSMR (BioFocus DPI) for Gli-Sufu Antagonist <i>ML340</i>. </p></div></div></div><div id="ml340.s14"><h4>e. Solubility and Stability of probe in PBS at room temperature</h4><p>The solubility of <a href="/pcsubstance/?term=ML340[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML340</a> was investigated in aqueous buffers at room temperature (see <a class="figpopup" href="/books/NBK158949/figure/ml340.f4/?report=objectonly" target="object" rid-figpopup="figml340f4" rid-ob="figobml340f4">Figure 4</a>). As noted in the <i>Summary of</i>
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<b><i>in vitro</i></b>
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<i>ADME/T properties</i> (see <a class="figpopup" href="/books/NBK158949/table/ml340.t7/?report=objectonly" target="object" rid-figpopup="figml340t7" rid-ob="figobml340t7">Table 7</a>), <a href="/pcsubstance/?term=ML340[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML340</a> has a poor solubility of 0.67 μg/mL in 137 mM NaCl, 2.7 mM KCl, 10 mM sodium phosphate dibasic, 2 mM potassium phosphate monobasic, pH 7.4 (PBS) at room temperature (23°C). The Chemical Stability was determined in 1xPBS, pH7.4/1xPBS and 50% ACN with 92.5% of the parent compound remaining after 48hrs. <a href="/pcsubstance/?term=ML340[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML340</a> appears very chemically stable when in solution (1:1 PBS:acetonitrile), and the apparent instability is rather a reflection of its poor aqueous solubility.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml340f4" co-legend-rid="figlgndml340f4"><a href="/books/NBK158949/figure/ml340.f4/?report=objectonly" target="object" title="Figure 4" class="img_link icnblk_img figpopup" rid-figpopup="figml340f4" rid-ob="figobml340f4"><img class="small-thumb" src="/books/NBK158949/bin/ml340f4.gif" src-large="/books/NBK158949/bin/ml340f4.jpg" alt="Figure 4. Stability of ML340 in PBS at ambient temperature." /></a><div class="icnblk_cntnt" id="figlgndml340f4"><h4 id="ml340.f4"><a href="/books/NBK158949/figure/ml340.f4/?report=objectonly" target="object" rid-ob="figobml340f4">Figure 4</a></h4><p class="float-caption no_bottom_margin">Stability of ML340 in PBS at ambient temperature. </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml340t7"><a href="/books/NBK158949/table/ml340.t7/?report=objectonly" target="object" title="Table 7" class="img_link icnblk_img figpopup" rid-figpopup="figml340t7" rid-ob="figobml340t7"><img class="small-thumb" src="/books/NBK158949/table/ml340.t7/?report=thumb" src-large="/books/NBK158949/table/ml340.t7/?report=previmg" alt="Table 7. Summary of in vitro ADME Properties of Gli-Sufu Antagonists Probe CID6538918." /></a><div class="icnblk_cntnt"><h4 id="ml340.t7"><a href="/books/NBK158949/table/ml340.t7/?report=objectonly" target="object" rid-ob="figobml340t7">Table 7</a></h4><p class="float-caption no_bottom_margin">Summary of <i>in vitro</i> ADME Properties of Gli-Sufu Antagonists Probe <i>CID6538918</i>. </p></div></div></div><div id="ml340.s15"><h4>f. Calculated and known probe properties: are shown in <a class="figpopup" href="/books/NBK158949/table/ml340.t3/?report=objectonly" target="object" rid-figpopup="figml340t3" rid-ob="figobml340t3">Table 3</a></h4><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml340t3"><a href="/books/NBK158949/table/ml340.t3/?report=objectonly" target="object" title="Table 3" class="img_link icnblk_img figpopup" rid-figpopup="figml340t3" rid-ob="figobml340t3"><img class="small-thumb" src="/books/NBK158949/table/ml340.t3/?report=thumb" src-large="/books/NBK158949/table/ml340.t3/?report=previmg" alt="Table 3. Calculated Properties for ML340 (CID 6020222)." /></a><div class="icnblk_cntnt"><h4 id="ml340.t3"><a href="/books/NBK158949/table/ml340.t3/?report=objectonly" target="object" rid-ob="figobml340t3">Table 3</a></h4><p class="float-caption no_bottom_margin">Calculated Properties for ML340 <i>(CID 6020222)</i>. </p></div></div></div><div id="ml340.s16"><h4>g. Provide MLS# that verifies the submission of probe molecule and five related samples that were submitted to the SMR collection</h4><p>Samples of the probe <a href="/pcsubstance/?term=ML340[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML340</a> (>25 mg), and five analogs of each (>20 mg), synthesized at SBCCG were submitted to MLSMR (<a class="figpopup" href="/books/NBK158949/table/ml340.t4/?report=objectonly" target="object" rid-figpopup="figml340t4" rid-ob="figobml340t4">Table 4</a>) and 5 mg of the probe were provided to the Assay Provider</p></div></div><div id="ml340.s17"><h3>2.3. Probe Preparation</h3><p><b>Preparation of N-(6-chloropyrimidin-4-yl)benzamide [2]</b>. (cmpds are numbered as in <a class="figpopup" href="/books/NBK158949/figure/ml340.f7/?report=objectonly" target="object" rid-figpopup="figml340f7" rid-ob="figobml340f7">Scheme 1</a>)</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml340f7" co-legend-rid="figlgndml340f7"><a href="/books/NBK158949/figure/ml340.f7/?report=objectonly" target="object" title="Scheme 1" class="img_link icnblk_img figpopup" rid-figpopup="figml340f7" rid-ob="figobml340f7"><img class="small-thumb" src="/books/NBK158949/bin/ml340f7.gif" src-large="/books/NBK158949/bin/ml340f7.jpg" alt="Scheme 1. Synthesis of ML340, conditions." /></a><div class="icnblk_cntnt" id="figlgndml340f7"><h4 id="ml340.f7"><a href="/books/NBK158949/figure/ml340.f7/?report=objectonly" target="object" rid-ob="figobml340f7">Scheme 1</a></h4><p class="float-caption no_bottom_margin">Synthesis of ML340, conditions. <i>a</i>. benzoyl chloride, DIPEA, DMAP, DCM, reflux, overnight (78%); <i>b</i>. 4-methylpiperidine, 80°C, 2 hours (60%). </p></div></div><div id="ml340.fu2" class="figure bk_fig"><div class="graphic"><img src="/books/NBK158949/bin/ml340fu2.jpg" alt="2." /></div><h3><span class="title">2</span></h3></div><p>6-chloropyrimidin-4-amine <b>1</b> (2.1 g, 16 mmol) and benzoyl chloride (2.3 g, 16 mmol) was dissolved in 100 ml of dichloromethane. The resulting mixture was added 3 ml of DIPEA and catalytic amount of DMAP, then refluxed at 50 °C overnight. When the reaction was determined to be complete by HPLC, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting oil was chromatographed on silica gel and eluted with ethyl acetate and hexane to yield 3.0 g of product <b>2</b> (78 % yield). ). <sup>1</sup>H NMR (400 MHz, CDCl3) δ(ppm) 7.52 (m, 2H), 7.62 (m, 1H), 7.90 (m, 2H), 8.43 (s, 1H), 8.55 (s, 1H), 8.96 (s, 1H). <sup>13</sup>C NMR (400 MHz, CDCl3) δ(ppm) 110.0, 127.4, 129.1, 132.9, 133.2, 158.0, 158.4, 162.6, 166.2. MS (EI) m/z 234 (M+1).</p><div id="ml340.fu3" class="figure"><div class="graphic"><img src="/books/NBK158949/bin/ml340fu3.jpg" alt="Image ml340fu3" /></div></div><p>N-(6-chloropyrimidin-4-yl)benzamide <b>2</b> (1.0 g, 4.3 mmol) and 4-methylpiperidine (0.85 g, 8.6 mmol) were heated at 80 °C for 2 hours. When the reaction was determined to be complete by HPLC, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting oil was triturated with methanol and filtered to yield <a href="/pcsubstance/?term=ML340[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML340</a> as a white solid 0.76 g (60 % yield). <sup>1</sup>H NMR (400 MHz, CDCl3) δ(ppm) 0.98 (m, 3H), 1.19 (m, 1H), 1.74 (m, 4H), 2.92 (m, 2H), 4.45 (m, 2H), 7.52 (m, 2H), 7.63 (m, 1H), 7.66 (m, 1H), 7.90 (m, 2H), 8.29 (s, 1H), 8.52 (s, 1H). <sup>13</sup>C NMR (400 MHz, CDCl3) δ(ppm) 21.8, 31.1, 33.8, 44.7, 90.0, 127.2, 128.9, 132.5, 133.9, 156.6, 157.6, 162.9, 166.3. MS (EI) m/z 297 (M+1). The characterization by <sup>1</sup>H NMR and HPLC/MS and the experimental details can be found in the Supplemental Appendices in <a href="#ml340.s44">Section 6.2</a>.</p></div></div><div id="ml340.s18"><h2 id="_ml340_s18_">3. Results</h2><div id="ml340.s19"><h3>3.1. Summary of Screening Results</h3><p>The flow chart in the <a class="figpopup" href="/books/NBK158949/figure/ml340.f5/?report=objectonly" target="object" rid-figpopup="figml340f5" rid-ob="figobml340f5">Figure 5</a> summarizes the hit identification, confirmation and validation for the Gli antagonist (Sufu-KO-LIGHT) screen. In summary, the Molecular Libraries Small Molecules Repository (MLSMR) collection comprising ~360,000 compounds was screened at 5 μM compound concentration in a final volume of 6 μL per well (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588413" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 588413</a>). The average Z′ for the screen was 0.75, the signal to background was 85, the signal to noise was 240, and the signal window was 5.9 as in <a class="figpopup" href="/books/NBK158949/table/ml340.t5/?report=objectonly" target="object" rid-figpopup="figml340t5" rid-ob="figobml340t5">Table 5</a>. These statistics indicate that the assay and screen behaved in a manner typical for a well-run cell based high throughput screen. With a cutoff of ≥55 % of inhibitory activity compared to the DMSO controls, 2,515 primary hits were identified, resulting in a 0.7 % hit rate, which is reasonable.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml340f5" co-legend-rid="figlgndml340f5"><a href="/books/NBK158949/figure/ml340.f5/?report=objectonly" target="object" title="Figure 5" class="img_link icnblk_img figpopup" rid-figpopup="figml340f5" rid-ob="figobml340f5"><img class="small-thumb" src="/books/NBK158949/bin/ml340f5.gif" src-large="/books/NBK158949/bin/ml340f5.jpg" alt="Figure 5. Screening hit triage." /></a><div class="icnblk_cntnt" id="figlgndml340f5"><h4 id="ml340.f5"><a href="/books/NBK158949/figure/ml340.f5/?report=objectonly" target="object" rid-ob="figobml340f5">Figure 5</a></h4><p class="float-caption no_bottom_margin">Screening hit triage. </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml340t5"><a href="/books/NBK158949/table/ml340.t5/?report=objectonly" target="object" title="Table 5" class="img_link icnblk_img figpopup" rid-figpopup="figml340t5" rid-ob="figobml340t5"><img class="small-thumb" src="/books/NBK158949/table/ml340.t5/?report=thumb" src-large="/books/NBK158949/table/ml340.t5/?report=previmg" alt="Table 5. Summary of Gli-antagonist (Sufu-KO-LIGHT) HTS Performance." /></a><div class="icnblk_cntnt"><h4 id="ml340.t5"><a href="/books/NBK158949/table/ml340.t5/?report=objectonly" target="object" rid-ob="figobml340t5">Table 5</a></h4><p class="float-caption no_bottom_margin">Summary of Gli-antagonist (Sufu-KO-LIGHT) HTS Performance. </p></div></div><p>Fresh stock solutions “cherry picks” of these 2,515 hits were requested from the MLSMR (Biofocus DPI) and 2,464 were received (98.0 %). These were then retested in the Sufu-KO-LIGHT confirmatory assay (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/602428" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 602428</a>) in triplicate at 5 μM resulting in 1056 confirmed (42.9 % confirmation) actives, based on at 1 of 3 retests being ≥45 % inhibition threshold. Subsequently, to triage these confirmed hits were tested in duplicate against a cytotoxicity counterscreen (ATPLite) and 550 hits (52.1 %) passed this. These were screened for selectivity against for antagonism of Wnt3a signaling pathway resulting in 345 compounds (62.7 %). This testing funnel, detailed previously and shown in <a class="figpopup" href="/books/NBK158949/figure/ml340.f5/?report=objectonly" target="object" rid-figpopup="figml340f5" rid-ob="figobml340f5">Figure 5</a>, excluded a total of 2119 compounds. Hit validation in 10-point dose response titration studies, using these 3 assays were performed on the remaining 345 compounds (Gli:AID <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/602464" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">602464</a>, cytotox-AID <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/651569" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">651569</a>, Wnt3a-AID <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/651570" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">651570</a>). These compounds were subject to further computational filters. Data mining of the PubChem and BCCG databases was performed to filter out hits that promiscuously inhibit other HTS assays. Our cheminformaticians applied cheminformatic filtering to eliminate known PAINS[<a class="bibr" href="#ml340.r39" rid="ml340.r39">39</a>,<a class="bibr" href="#ml340.r40" rid="ml340.r40">40</a>] (<u>P</u>an <u>A</u>ssay <u>I</u>nterference Compound<u>s</u>). Additionally, our experienced project chemists visually inspected the chemical structures of the filtered hits and eliminated any compounds they judged were <i>a priori</i> undesirable, intractable or were previously problematic in other screens and projects based on these experimental results and informatic analysis, dry powder compounds were selected for follow up studies and additional, commercially available analogues were ordered.</p></div><div id="ml340.s20"><h3>3.2. Dose Response Curves for Probe</h3><div id="ml340.f6" class="figure bk_fig"><div class="graphic"><img src="/books/NBK158949/bin/ml340f6.jpg" alt="Figure 6. Dose response curve for ML340 in the cell-based Gli antagonist (Sufu-KO-LIGHT) assay." /></div><h3><span class="label">Figure 6</span><span class="title">Dose response curve for ML340 in the cell-based Gli antagonist (Sufu-KO-LIGHT) assay</span></h3></div></div><div id="ml340.s21"><h3>3.3. Scaffold/Moiety Chemical Liabilities</h3><p>This scaffold contains no reactive moieties or functional groups known to form covalent bonds, and appears stable in aqueous buffer, though is rather insoluble (<a class="figpopup" href="/books/NBK158949/figure/ml340.f3/?report=objectonly" target="object" rid-figpopup="figml340f3" rid-ob="figobml340f3">Figure 3</a>). The amide bond linking the two hemispheres of the probe molecule may provide a facile site for metabolism of the compound <i>in vivo.</i> These predictions are verified by the values obtained for the <i>in vitro</i> ADME/T panel (<a class="figpopup" href="/books/NBK158949/table/ml340.t7/?report=objectonly" target="object" rid-figpopup="figml340t7" rid-ob="figobml340t7">Table 7</a>. in <a href="#ml340.s24">Section 3.6</a>) showing poor aqueous solubility, moderate lability in plasma and poor stability in liver microsomes.</p></div><div id="ml340.s22"><h3>3.4. SAR Analysis</h3><p>From the original hit series we found several promising scaffolds. We focused our efforts on the pyrimidine series represented by <b>CID 1540596</b> (see Entry 1, <a class="figpopup" href="/books/NBK158949/table/ml340.t6/?report=objectonly" target="object" rid-figpopup="figml340t6" rid-ob="figobml340t6">Table 6</a>, 1<sup>st</sup> line, CP <i>= MLSMR cherry pick</i>). In the initial screen, <b>CID 1540596</b> was one of the most potent compounds screened to date, IC<sub>50</sub> = 295 nM, when retested from freshly supplied 10 mM DMSO stocks from the NIH MLSMR. Subsequently, we purchased this from a commercial supplier and found the powder to be ~ 5–10 fold more potent at 56.5 and 22.9 nM (see Entry 1, <a class="figpopup" href="/books/NBK158949/table/ml340.t6/?report=objectonly" target="object" rid-figpopup="figml340t6" rid-ob="figobml340t6">Table 6</a>, 2<sup>nd</sup> line, P <i>= purchased</i>). In addition, the Assay Provider’s lab (Prof. Chen, Stanford) tested this compound independently and obtained an IC<sub>50</sub> ~ 35 nM. We independently synthesized this compound during the course of rounds of analog-by-catalog (ABC) and medicinal chemistry synthesis and SAR. The resynthesized batch of <b>CID 1540596</b> had an IC<sub>50</sub> of 24.2 nM. Overall, we synthesized 57 compounds in the pyrimidine series, to ultimately select <a href="/pcsubstance/?term=ML340[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML340</a> (CID 65389180) as our probe with the consistently lowest IC<sub>50</sub> (33.6 ± 4.3 nM) and selectivity against Wnt3a. The following narrative and <a class="figpopup" href="/books/NBK158949/table/ml340.t6/?report=objectonly" target="object" rid-figpopup="figml340t6" rid-ob="figobml340t6">Table 6</a> detail the SAR explorations.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml340t6"><a href="/books/NBK158949/table/ml340.t6/?report=objectonly" target="object" title="Table 6" class="img_link icnblk_img figpopup" rid-figpopup="figml340t6" rid-ob="figobml340t6"><img class="small-thumb" src="/books/NBK158949/table/ml340.t6/?report=thumb" src-large="/books/NBK158949/table/ml340.t6/?report=previmg" alt="Table 6. SAR explorations of ML340." /></a><div class="icnblk_cntnt"><h4 id="ml340.t6"><a href="/books/NBK158949/table/ml340.t6/?report=objectonly" target="object" rid-ob="figobml340t6">Table 6</a></h4><p class="float-caption no_bottom_margin">SAR explorations of ML340. </p></div></div><div id="ml340.fu4" class="figure"><div class="graphic"><img src="/books/NBK158949/bin/ml340fu22.jpg" alt="Image ml340fu22" /></div></div><p>Our initial SAR strategy for this series of molecules involves investigating the effects of changing the piperidine ring (R<sub>1</sub>) of <b>CID 1540596</b> to other ring systems including pyrrolidine (Entry 3), morpholino (Entry 33), thiomorpholine (Entry 29), piperazine (Entry 40), and N-methylpiperazine (Entry 31), all of these analogs are less potent than <b>CID 1540596</b>. When we replaced the piperidine ring with an azepane (Entry 28) or 4-methylpiperidine (Entry 39) the activity of the series was comparable to <b>CID 1540596</b> IC<sub>50</sub> = 61.2 nM and 33.6 nM respectively. Substitution of various alkyl amines (Entries 4, 16, 17, 32, 34, 35, 37, 38) for the piperidine produced compounds with reduced potency versus <b>CID 1540596</b>.</p><div id="ml340.fu5" class="figure"><div class="graphic"><img src="/books/NBK158949/bin/ml340fu23.jpg" alt="Image ml340fu23" /></div></div><p>When we retained the piperidine ring (R<sub>1</sub>) of <b>CID 1540596</b> and changed the R<sub>2</sub> group we found that substitution of electron donating groups or electron-withdrawing group on the pendant phenyl ring the potency of the compounds increased (Entries 2, 7, 10, 20, 43–50, 52). Substitution of the phenyl group with a thiophene ring (Entries 54 and 55), furan (Entry 51), naphthalene ring (Entries 56 and 57) or the 2-benzo-thiophene group (Entry 55) resulted in compounds with less activity than <b>CID 1540596</b>.</p><p>We synthesized several compounds where a methyl group was substituted for a hydrogen atom on the pyrimidine ring at the C-2 position. For example, Entries 1 and 14, the compound with the methyl group was substantially less potent, IC<sub>50</sub> = 24.2 nM versus IC<sub>50</sub> > 11.7 μM. The Probe Compound <a href="/pcsubstance/?term=ML340[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML340</a>, we selected is Entry 39 as it was the most potent compound synthesized, IC<sub>50</sub> = 33.6 nM and displayed 64.9 fold selectivity for inhibiting Gli transcription <i>versus</i> the Wnt signaling assay.</p></div><div id="ml340.s23"><h3>3.5. Cellular Activity</h3><p>All of the functional assay describe that support this project are cell-based and therefore this probe does demonstrate efficacy in antagonizing the Gli function in live cells, while not exhibiting general cytotoxity, and is not antagonistic to the Wnt3a pathway. We do note however, the probe and some of the close analogs exhibit some strong direct activation (rather than inhibition) of Wnt3a signaling at concentrations > 1000 nM. Similarly, the Hh reporter activity begins to increase at these elevated compound levels. We hypothesize that this reflects a non-specific off-target effect manifested at higher compound doses.</p></div><div id="ml340.s24"><h3>3.6. Profiling Assays</h3><p><b><i>In vitro Pharmacology Profiles</i></b> conducted by SBCCG Exploratory Pharmacology group of Probe <b>CID6538918</b> [<a href="/pcsubstance/?term=ML340[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML340</a>] (<i>See</i>
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|
<a class="figpopup" href="/books/NBK158949/table/ml340.t7/?report=objectonly" target="object" rid-figpopup="figml340t7" rid-ob="figobml340t7">Table 7</a>).</p><p><a href="/pcsubstance/?term=ML340[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML340</a> has poor solubility in aqueous media 0.84, 0.62 μg/mL, 0.72 μg/mL at pH 5.0, 6.2 and 7.4 respectively.</p><p>The <b>PAMPA</b> (<b>P</b>arallel <b>A</b>rtificial <b>M</b>embrane <b>P</b>ermeability <b>A</b>ssay) assay is used as an <b><i>in vitro</i></b> model of passive, transcellular permeability. An artificial membrane immobilized on a filter is placed between a donor and acceptor compartment. At the start of the test, drug is introduced in the donor compartment. Following the permeation period, the concentration of drug in the donor and acceptor compartments is measured using UV spectroscopy. Consistent with the predicted LogP (see <a class="figpopup" href="/books/NBK158949/table/ml340.t3/?report=objectonly" target="object" rid-figpopup="figml340t3" rid-ob="figobml340t3">Table 3</a>), <a href="/pcsubstance/?term=ML340[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML340</a> is very permeable at pH 5.0 and highly permeable at pH 6.2 and 7.4 in this assay.</p><p><b>Plasma Protein Binding</b> is a measure of a drug’s efficiency to bind to the proteins within blood plasma. The less bound a drug is, the more efficiently it can traverse cell membranes or diffuse. Highly plasma protein bound drugs are confined to the vascular space, thereby having a relatively low volume of distribution. In contrast, drugs that remain largely unbound in plasma are generally available for distribution to other organs and tissues. <a href="/pcsubstance/?term=ML340[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML340</a> shows high binding to plasma proteins in both mouse and human plasma.</p><p><b>Stability in PBS and in 1:1 PBS Acetonitrile.</b> As <a href="/pcsubstance/?term=ML340[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML340</a> is very insoluble in PBS, and <a href="/pcsubstance/?term=ML340[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML340</a> is apparently fairly stable in PBS and completely stable in 1:1 PBS:Acetonitrile with 57.21 % and 92.54 % of parent <a href="/pcsubstance/?term=ML340[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML340</a> remaining after 48 hrs. of incubation at ambient temperature.</p><p><b>Plasma Stability</b> is a measure of the stability of small molecules and peptides in plasma and is an important parameter, which strongly can influence the <b><i>in vivo</i></b> efficacy of a test compound. Drug candidates are exposed in plasma to enzymatic processes (proteinases, esterases), and they can undergo intramolecular rearrangement or bind irreversibly (covalently) to proteins. <a href="/pcsubstance/?term=ML340[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML340</a> shows very good stability in human (85.04 % remaining at 3 hrs) and moderate stability (39.54 % remaining at 3 hrs) in mouse plasma.</p><p>The microsomal stability assay is commonly used to rank compounds according to their metabolic stability. This assay addresses the pharmacologic question of how long the parent compound will remain circulating in plasma within the body. <a href="/pcsubstance/?term=ML340[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML340</a> shows poor stability in both human and mouse liver microsomes, potentially limiting the utility of this probe in <b><i>in vivo</i></b> rodent models and in a human therapeutic context. This is one area of needed improvement for future PK optimization approaches.</p><p><a href="/pcsubstance/?term=ML340[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML340</a> exhibits no toxicity (LC<sub>50</sub> > 50 μM) towards immortalized Fa2-N4 human hepatocytes.</p></div></div><div id="ml340.s25"><h2 id="_ml340_s25_">4. Discussion</h2><div id="ml340.s26"><h3>4.1. Comparison to existing art and how the new probe is an improvement</h3><p>In this report we have identified the most potent Gli-Sufu Antagonists, in the literature to date. <a href="/pcsubstance/?term=ML340[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML340</a> (CID 6538918) IC<sub>50</sub> = 33.6 nM. <a href="/pcsubstance/?term=ML340[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML340</a> is more potent than any known compound in the literature and it is chemically stable and will serve as a unique biochemical probe.</p><p>Nearly all known Hh pathway inhibitors target the transmembrane protein Smo, and therefore probes that act on downstream signaling proteins are needed. <a href="/pcsubstance/?term=ML340[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML340</a> is a small molecule that is epistatic to the Gli antagonist Sufu, providing a compound for studying the mechanisms that regulate Gli transcription factor function and structural leads for new Hh pathway-targeting anti-cancer therapies. This compound will be particularly valuable to the developmental biology and cancer biology communities, as the biochemical and cellular processes that control Gli activity state remain elusive and Hh pathway-dependent tumors that acquire resistance to Smo antagonists have been observed in the clinic.</p></div><div id="ml340.s27"><h3>4.2. Mechanism of Action Studies</h3><p>Mechanism of action studies are planned as future studies (see <a href="#ml340.s28">Section 4.3</a>).</p></div><div id="ml340.s28"><h3>4.3. Planned Future Studies</h3><p>Having identified <a href="/pcsubstance/?term=ML340[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML340</a> as a potent antagonist of Gli function, we will investigate its mechanism of action through a variety of cell-based assays. We will first confirm its epistatic relationship with other Hh pathway components by evaluating its efficacy against Hh target gene expression induced by Shh, the small-molecule Smo agonist SAG, <i>Gli1</i> overexpression, or <i>Gli2</i> overexpression. If <a href="/pcsubstance/?term=ML340[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML340</a> can inhibit exogenous Gli1 and/or Gli2 function, we will assess the degree to which it can discern between these two transcription factor isoforms. This will be achieved by expressing the individual Gli genes in mutant murine fibroblasts lacking the other isoform.</p><p>The effects of <a href="/pcsubstance/?term=ML340[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML340</a> on Gli state will then be determined. For example, Gli3 can be electrophoretically resolved into its N-terminal repressor, full-length, and phosphorylated full-length activator states, and we will investigate whether the compound alters Gli3 state in the absence or presence of Shh stimulation. Similarly, Gli2 trafficking in response to Shh treatment can be followed by immunocytochemistry, and we will determine whether <a href="/pcsubstance/?term=ML340[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML340</a> prevents the Shh-induced accumulation of Gli2 in the primary cilium. Other aspects of Gli function can also be interrogated, including its association with Sufu, various post-translational modifications associated with Gli regulation, and its ability to bind DNA.</p></div></div><div id="ml340.s29"><h2 id="_ml340_s29_">5. References</h2><dl class="temp-labeled-list"><dl class="bkr_refwrap"><dt>1.</dt><dd><div class="bk_ref" id="ml340.r1">Wechsler-Reya R, Scott MP. The developmental biology of brain tumors. <span><span class="ref-journal">Annu Rev Neurosci. </span>2001;<span class="ref-vol">24</span>:385–428.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11283316" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11283316</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>2.</dt><dd><div class="bk_ref" id="ml340.r2">Jiang J, Hui C-c. Hedgehog signaling in development and cancer. <span><span class="ref-journal">Dev Cell. </span>2008;<span class="ref-vol">15</span>:801–812.</span> [<a href="/pmc/articles/PMC6443374/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6443374</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19081070" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19081070</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>3.</dt><dd><div class="bk_ref" id="ml340.r3">Yauch RL, Gould SE, Scales SJ, Tang T, Tian H, Ahn CP, Marshall D, Fu L, Januario T, Kallop D, Nannini-Pepe M, Kotkow K, Marsters JC, Rubin LL, de Sauvage FJ. A paracrine requirement for hedgehog signalling in cancer. <span><span class="ref-journal">Nature. </span>2008;<span class="ref-vol">455</span>:406–410.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18754008" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18754008</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>4.</dt><dd><div class="bk_ref" id="ml340.r4">Watkins DN, Berman DM, Burkholder SG, Wang B, Beachy PA, Baylin SB. Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer. <span><span class="ref-journal">Nature. </span>2003;<span class="ref-vol">422</span>:313–317.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12629553" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12629553</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>5.</dt><dd><div class="bk_ref" id="ml340.r5">Wolter M, Reifenberger J, Sommer C, Ruzicka T, Reifenberger G. Mutations in the human homologue of the Drosophila segment polarity gene patched (PTCH) in sporadic basal cell carcinomas of the skin and primitive neuroectodermal tumors of the central nervous system. <span><span class="ref-journal">Cancer Ress. </span>1997;<span class="ref-vol">57</span>:2581–2585.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9205058" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9205058</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>6.</dt><dd><div class="bk_ref" id="ml340.r6">Xie J, Johnson RL, Zhang X, Bare JW, Waldman FM, Cogen PH, Menon AG, Warren RS, Chen LC, Scott MP, Epstein EH Jr. Mutations of the PATCHED gene in several types of sporadic extracutaneous tumors. <span><span class="ref-journal">Cancer Res. </span>1997;<span class="ref-vol">57</span>:2369–2372.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9192811" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9192811</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>7.</dt><dd><div class="bk_ref" id="ml340.r7">Xie J, Murone M, Luoh SM, Ryan A, Gu Q, Zhang C, Bonifas JM, Lam CW, Hynes M, Goddard A, Rosenthal A, Epstein EH Jr, de Sauvage FJ. Activating Smoothened mutations in sporadic basal-cell carcinoma. <span><span class="ref-journal">Nature. </span>1998;<span class="ref-vol">391</span>:90–92.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9422511" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9422511</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>8.</dt><dd><div class="bk_ref" id="ml340.r8">Vorechovsky I, Tingby O, Hartman M, Stromberg B, Nister M, Collins VP, Toftgard R. Somatic mutations in the human homologue of Drosophila patched in primitive neuroectodermal tumours. <span><span class="ref-journal">Oncogene. </span>1997;<span class="ref-vol">15</span>:361–366.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9233770" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9233770</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>9.</dt><dd><div class="bk_ref" id="ml340.r9">Goodrich LV, Milenkovic L, Higgins KM, Scott MP. Altered neural cell fates and medulloblastoma in mouse patched mutants. <span><span class="ref-journal">Science. </span>1997;<span class="ref-vol">277</span>:1109–1113.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9262482" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9262482</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>10.</dt><dd><div class="bk_ref" id="ml340.r10">Reifenberger J, Wolter M, Weber RG, Megahed M, Ruzicka T, Lichter P, Reifenberger G. Missense mutations in SMOH in sporadic basal cell carcinomas of the skin and primitive neuroectodermal tumors of the central nervous system. <span><span class="ref-journal">Cancer Res. </span>1998;<span class="ref-vol">58</span>:1798–1803.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9581815" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9581815</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>11.</dt><dd><div class="bk_ref" id="ml340.r11">Taylor MD, Liu L, Raffel C, Hui CC, Mainprize TG, Zhang X, Agatep R, Chiappa S, Gao L, Lowrance A, Hao A, Goldstein AM, Stavrou T, Scherer SW, Dura WT, Wainwright B, Squire JA, Rutka JT, Hogg D. Mutations in SUFU predispose to medulloblastoma. <span><span class="ref-journal">Nat Genet. </span>2002;<span class="ref-vol">31</span>:306–310.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12068298" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12068298</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>12.</dt><dd><div class="bk_ref" id="ml340.r12">Mahindroo N, Punchihewa C, Fujii N. Hedgehog-Gli signaling pathway inhibitors as anticancer agents. <span><span class="ref-journal">J Med Chem. </span>2009;<span class="ref-vol">52</span>:3829–3845.</span> [<a href="/pmc/articles/PMC2743241/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2743241</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19309080" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19309080</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>13.</dt><dd><div class="bk_ref" id="ml340.r13">Berman D, Karhadkar S, Hallahan A, Pritchard J, Eberhart C, Watkins D, Chen J, Cooper M, Taipale J, Olson J, Beachy P. Medulloblastoma growth inhibition by hedgehog pathway blockade. <span><span class="ref-journal">Science. </span>2002;<span class="ref-vol">297</span>:1559–1561.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12202832" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12202832</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>14.</dt><dd><div class="bk_ref" id="ml340.r14">Lucas BS, Aaron W, An S, Austin RJ, Brown M, Chan H, Chong A, Hungate R, Huang T, Jiang B, Johnson MG, Kaizerman JA, Lee G, McMinn DL, Orf J, Powers JP, Rong M, Toteva MM, Uyeda C, Wickramasinghe D, Xu G, Ye Q, Zhong W. Design of 1- piperazinyl-4-arylphthalazines as potent Smoothened antagonists. <span><span class="ref-journal">Bioorg Med Chem Lett. </span>2010;<span class="ref-vol">20</span>:3618–3622.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/20493695" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20493695</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>15.</dt><dd><div class="bk_ref" id="ml340.r15">Miller-Moslin K, Peukert S, Jain R, McEwan M, Karki R, Llamas L, Yusuff N, He F, Li Y, Sun Y, Dai M, Perez L, Michael W, Sheng T, Lei H, Zhang R, Williams J, Bourret A, Ramamurthy A, Yuan J, Guo R, Matsumoto M, Vattay A, Maniara W, Amaral A, Dorsch M, Kelleher J. 1-amino-4-benzylphthalazines as orally bioavailable smoothened antagonists with antitumor activity. <span><span class="ref-journal">J Med Chem. </span>2009;<span class="ref-vol">52</span>:3954–3968.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/19469545" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19469545</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>16.</dt><dd><div class="bk_ref" id="ml340.r16">Pan S, Wu X, Jiang J, Gao W, Wan Y, Cheng D. Discovery of NVP-LDE225, a Potent and Selective Smoothened Antagonist. <span><span class="ref-journal">ACS Medicinal Chemistry. </span>2010</span> [<a href="/pmc/articles/PMC4007689/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4007689</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24900187" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24900187</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>17.</dt><dd><div class="bk_ref" id="ml340.r17">Robarge KD, Brunton SA, Castanedo GM, Cui Y, Dina MS, Goldsmith R, Gould SE, Guichert O, Gunzner JL, Halladay J, Jia W, Khojasteh C, Koehler MF, Kotkow K, La H, Lalonde RL, Lau K, Lee L, Marshall D, Marsters JC Jr, Murray LJ, Qian C, Rubin LL, Salphati L, Stanley MS, Stibbard JH, Sutherlin DP, Ubhayaker S, Wang S, Wong S, Xie M. GDC-0449-a potent inhibitor of the hedgehog pathway. <span><span class="ref-journal">Bioorg Med Chem Lett. </span>2009;<span class="ref-vol">19</span>:5576–5581.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/19716296" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19716296</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>18.</dt><dd><div class="bk_ref" id="ml340.r18">Romer JT, Kimura H, Magdaleno S, Sasai K, Fuller C, Baines H, Connelly M, Stewart CF, Gould S, Rubin LL, Curran T. Suppression of the Shh pathway using a small molecule inhibitor eliminates medulloblastoma in Ptc1(+/−)p53(−/−) mice. <span><span class="ref-journal">Cancer Cell. </span>2004;<span class="ref-vol">6</span>:229–240.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15380514" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15380514</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>19.</dt><dd><div class="bk_ref" id="ml340.r19">Tremblay M, Lescarbeau A, Grogan M, Tan E, Lin G, Austad B, Yu L, Behnke M, Nair S, Hagel M, White K, Conley J, Manna J, Alvarez-Diez T, Hoyt J, Woodward C, Sydor J, Pink M, MacDougall J, Campbell M, Cushing J, Ferguson J, Curtis M, McGovern K, Read M, Palombella V, Adams J, Castro A. Discovery of a potent and orally active hedgehog pathway antagonist (IPI-926). <span><span class="ref-journal">J Med Chem. </span>2009;<span class="ref-vol">52</span>:4400–4418.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/19522463" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19522463</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>20.</dt><dd><div class="bk_ref" id="ml340.r20">Von Hoff DD, LoRusso PM, Rudin CM, Reddy JC, Yauch RL, Tibes R, Weiss GJ, Borad MJ, Hann CL, Brahmer JR, Mackey HM, Lum BL, Darbonne WC, Marsters JC, de Sauvage FJ, Low JA. Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. <span><span class="ref-journal">N Engl J Med. </span>2009;<span class="ref-vol">361</span>:1164–1172.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/19726763" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19726763</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>21.</dt><dd><div class="bk_ref" id="ml340.r21">Yauch RL, Dijkgraaf GJP, Alicke B, Januario T, Ahn CP, Holcomb T, Pujara K, Stinson J, Callahan CA, Tang T, Bazan JF, Kan Z, Seshagiri S, Hann CL, Gould SE, Low JA, Rudin CM, de Sauvage FJ. Smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma. <span><span class="ref-journal">Science. </span>2009;<span class="ref-vol">326</span>:572–574.</span> [<a href="/pmc/articles/PMC5310713/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5310713</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19726788" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19726788</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>22.</dt><dd><div class="bk_ref" id="ml340.r22">Chen J, Taipale J, Cooper M, Beachy P. Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened. <span><span class="ref-journal">Genes Dev. </span>2002;<span class="ref-vol">16</span>:2743–2748.</span> [<a href="/pmc/articles/PMC187469/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC187469</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/12414725" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12414725</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>23.</dt><dd><div class="bk_ref" id="ml340.r23">Joo J, Christensen L, Warner K, States L, Kang H-G, Vo K, Lawlor ER, May WA. GLI1 is a central mediator of EWS/FLI1 signaling in Ewing tumors. <span><span class="ref-journal">PLoS One. </span>2009;<span class="ref-vol">4</span>:e7608.</span> [<a href="/pmc/articles/PMC2763206/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2763206</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19859563" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19859563</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>24.</dt><dd><div class="bk_ref" id="ml340.r24">Ji Z, Mei FC, Xie J, Cheng X. Oncogenic KRAS activates hedgehog signaling pathway in pancreatic cancer cells. <span><span class="ref-journal">J Biol Chem. </span>2007;<span class="ref-vol">282</span>:14048–14055.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17353198" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17353198</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>25.</dt><dd><div class="bk_ref" id="ml340.r25">Nolan-Stevaux O, Lau J, Truitt ML, Chu GC, Hebrok M, Fernández-Zapico ME, Hanahan D. GLI1 is regulated through Smoothened-independent mechanisms in neoplastic pancreatic ducts and mediates PDAC cell survival and transformation. <span><span class="ref-journal">Genes Dev. </span>2009;<span class="ref-vol">23</span>:24–36.</span> [<a href="/pmc/articles/PMC2632164/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2632164</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19136624" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19136624</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>26.</dt><dd><div class="bk_ref" id="ml340.r26">Dennler S, André J, Verrecchia F, Mauviel A. Cloning of the human GLI2 Promoter: transcriptional activation by transforming growth factor-beta via SMAD3/beta-catenin cooperation. <span><span class="ref-journal">J Biol Chem. </span>2009;<span class="ref-vol">284</span>:31523–31531.</span> [<a href="/pmc/articles/PMC2797221/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2797221</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19797115" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19797115</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>27.</dt><dd><div class="bk_ref" id="ml340.r27">Beauchamp E, Bulut G, Abaan O, Chen K, Merchant A, Matsui W, Endo Y, Rubin JS, Toretsky J, Uren A. GLI1 is a direct transcriptional target of EWS-FLI1 oncoprotein. <span><span class="ref-journal">J Biol Chem. </span>2009;<span class="ref-vol">284</span>:9074–9082.</span> [<a href="/pmc/articles/PMC2666556/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2666556</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19189974" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19189974</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>28.</dt><dd><div class="bk_ref" id="ml340.r28">Chen J, Taipale J, Young K, Maiti T, Beachy P. Small molecule modulation of Smoothened activity. <span><span class="ref-journal">Proc Natl Acad Sci U S A. </span>2002;<span class="ref-vol">99</span>:14071–14076.</span> [<a href="/pmc/articles/PMC137838/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC137838</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/12391318" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12391318</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>29.</dt><dd><div class="bk_ref" id="ml340.r29">Hyman J, Firestone A, Heine V, Zhao Y, Ocasio C, Han K, Sun M, Rack P, Sinha S, Wu J, Solow-Cordero D, Jiang J, Rowitch D, Chen J. Small-molecule inhibitors reveal multiple strategies for Hedgehog pathway blockade. <span><span class="ref-journal">Proc Natl Acad Sci U S A. </span>2009;<span class="ref-vol">106</span>:14132–7.</span> [<a href="/pmc/articles/PMC2721821/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2721821</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19666565" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19666565</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>30.</dt><dd><div class="bk_ref" id="ml340.r30">Lauth M, Bergstrom A, Shimokawa T, Toftgard R. Inhibition of GLI-mediated transcription and tumor cell growth by small-molecule antagonists. <span><span class="ref-journal">Proc Natl Acad Sci U S A. </span>2007;<span class="ref-vol">104</span>:8455–8460.</span> [<a href="/pmc/articles/PMC1866313/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1866313</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/17494766" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17494766</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>31.</dt><dd><div class="bk_ref" id="ml340.r31">Arai M, Tateno C, Hosoya T, Koyano T, Kowithayakorn T, Ishibashi M. Hedgehog/GLImediated transcriptional inhibitors from Zizyphus cambodiana. <span><span class="ref-journal">Bioorg Med Chem. </span>2008;<span class="ref-vol">16</span>:9420–9424.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18842418" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18842418</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>32.</dt><dd><div class="bk_ref" id="ml340.r32">Hosoya T, Arai M, Koyano T, Kowithayakorn T, Ishibashi M. Naturally occurring smallmolecule inhibitors of hedgehog/GLI-mediated transcription. <span><span class="ref-journal">Chembiochem. </span>2008;<span class="ref-vol">9</span>:1082–1092.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18357592" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18357592</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>33.</dt><dd><div class="bk_ref" id="ml340.r33">Teglund S, Toftgard R. Hedgehog beyond medulloblastoma and basal cell carcinoma. <span><span class="ref-journal">Biochim Biophys Acta. </span>2010;<span class="ref-vol">1805</span>:181–208.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/20085802" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20085802</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>34.</dt><dd><div class="bk_ref" id="ml340.r34">Rifai Y, Arai MA, Koyano T, Kowithayakorn T, Ishibashi M. Terpenoids and a flavonoid glycoside from Acacia pennata leaves as hedgehog/GLI-mediated transcriptional inhibitors. <span><span class="ref-journal">J Nat Prod. </span>2010;<span class="ref-vol">73</span>:995–997.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/20450170" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20450170</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>35.</dt><dd><div class="bk_ref" id="ml340.r35">Arai MA, Tateno C, Koyano T, Kowithayakorn T, Kawabe S, Ishibashi M. New hedgehog/GLI-signaling inhibitors from Adenium obesum. <span><span class="ref-journal">Org Biomol Chem. </span>2011;<span class="ref-vol">9</span>:1133–1139.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/21170436" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21170436</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>36.</dt><dd><div class="bk_ref" id="ml340.r36">Rifai Y, Arai MA, Sadhu SK, Ahmed F, Ishibashi M. New Hedgehog/GLI signaling inhibitors from Excoecaria agallocha. <span><span class="ref-journal">Bioorg Med Chem Lett. </span>2011;<span class="ref-vol">21</span>:718–722.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/21190854" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21190854</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>37.</dt><dd><div class="bk_ref" id="ml340.r37">Actis M, Connelly MC, Mayasundari A, Punchihewa C, Fujii N. A structure-activity relationship study of small-molecule inhibitors of GLI1-mediated transcription. <span><span class="ref-journal">Biopolymers. </span>2011;<span class="ref-vol">95</span>:24–30.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/20872873" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20872873</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>38.</dt><dd><div class="bk_ref" id="ml340.r38">Mahindroo N, Connelly MC, Punchihewa C, Yang L, Yan B, Fujii N. Amide conjugates of ketoprofen and indole as inhibitors of Gli1-mediated transcription in the Hedgehog pathway. <span><span class="ref-journal">Bioorg Med Chem. </span>2010;<span class="ref-vol">18</span>:4801–4811.</span> [<a href="/pmc/articles/PMC2952073/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2952073</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20605720" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20605720</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>39.</dt><dd><div class="bk_ref" id="ml340.r39">Baell JB, Holloway GA. New Substructure Filters for Removal of Pan Assay Interference Compounds (PAINS) from Screening Libraries and for Their Exclusion in Bioassays. <span><span class="ref-journal">J Med Chem. </span>2010;<span class="ref-vol">53</span>:2719–274.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/20131845" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20131845</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>40.</dt><dd><div class="bk_ref" id="ml340.r40">Baell JB. Observations on screening-based research and some concerning trends in the literature. <span><span class="ref-journal">Future Med Chem. </span>2010;<span class="ref-vol">2</span>(10):1529–1546.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/21426147" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21426147</span></a>]</div></dd></dl></dl></div><div id="ml340.s30"><h2 id="_ml340_s30_">6. Supplementary Information</h2><div id="ml340.s31"><h3>6.1. Assay Details</h3><div id="ml340.s32"><h4>Primary Assay - Gli Antagonist Primary Screen Procedure</h4><div id="ml340.s33"><h5>Cell Culture</h5><div id="ml340.s34"><h5>Media</h5><div id="ml340.s35"><h5>Sufu-KO-LIGHT cell line GROWTH MEDIUM</h5><p>Final concentrations</p><p>DMEM Phenol Red containing (Hyclone #SH30243.02)</p><p>HI-FBS characterized (Hyclone SH30396.03 HI or equivalent) 10%</p><p>L-glutamine (Cellgro # 25-005-CI) 200 mM 100 mL 2 mM (1:100)</p><p>Penn/Strep (Cellgro #30-0020CI) 5000 IU/mL 100 mL 50 IU/mL (1:100)</p><p>Zeocin (Invitrogen <a href="/nuccore/779893" class="bk_tag" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=nuccore">R25005</a> or Sigma 46-0072) 5 g in 50 mL (100 mg/mL) 0.15 mg/mL (1:666.67)</p></div><div id="ml340.s36"><h5>Sufu-KO-LIGHT cell line ASSAY MEDIUM</h5><p>Final concentrations</p><p>DMEM phenol red free (Hyclone SH30585.02)</p><p>HI-FBS characterized (HYCLONE SH30396.03 HI or equivalent) 10%</p><p>L-glutamine (Cellgro # 25-005-CI) 200 mM 100 mL 2 mM (1:100)</p><p>Na-pyruvate (Sigma S8636-100ML) 100 mM 1 mM (1:100)</p><p>Penn/Strep (Cellgro #30-0020CI) 5000 IU/mL 100mL 50 IU/mL(1:100)</p><p>HEPES (Omega Scientific # HB-20) 100 mL 1 M 25 mM (1:40)</p><p>Zeocin (Invitrogen <a href="/nuccore/779893" class="bk_tag" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=nuccore">R25005</a> or Sigma 46-0072) 5g in 50 mL (100 mg/mL) 0.15 mg/mL (1:666.67)</p></div></div><div id="ml340.s37"><h5>Other Reagents</h5><p>Sufu-KO-LIGHT cell line (Assay Provider)</p><p>PBS (Phosphate Buffered Saline)</p><p>TrypLE™ Express cell dissociation reagent (Life Technologies)</p><p>T225 tissue culture flasks (Corning)</p><p>HYPERflasks ® (Corning)</p><p>1536 well tissue culture plates Aurora (c) & Corning</p><p>1536 well Echo® compatible Cyclic Olefin Copolymer (COC) compound storage plates (Corning or Labcyte)</p><p>384 well low volume Echo® compatible COC compound storage plates (labcyte)</p><p>Bright-Glo™luciferase detection reagent (Promega)</p></div></div><div id="ml340.s38"><h5>Automation & Instrumentation</h5><p>HighRes Biosolutions (HRB) MicroStar robotics platform with Cellario™ scheduling software integrating the following instruments:</p><ul><li class="half_rhythm"><div>Viewlux™ microplate imager (PerkinElmer)</div></li><li class="half_rhythm"><div>VSpin™ microplate centrifuge (Velocity11/Agilent)</div></li><li class="half_rhythm"><div>Multidrop Combi liquid handler/dispenser (Thermo)</div></li><li class="half_rhythm"><div>Liconic tissue culture incubator (Liconic)</div></li><li class="half_rhythm"><div>Echo® 550 acoustic liquid handler (Labcyte)</div></li></ul><div id="ml340.s39"><h5>Other instrumentation</h5><ul><li class="half_rhythm"><div>Biotek Microflo™ Select peristaltic liquid handler/dispenser</div></li><li class="half_rhythm"><div>Thermo Centra CL2 Clinical Centrifuge</div></li><li class="half_rhythm"><div>Nexcelom Bioscience Cellometer® Auto T4 cell counter</div></li><li class="half_rhythm"><div>Eppendorf 5810 centrifuge</div></li></ul></div></div><div id="ml340.s40"><h5>Assay Procedure</h5><div id="ml340.s41"><h5>Day 1</h5><ol><li class="half_rhythm"><div>Cells harvested from 2 hyperflasks at 80–90% confluency per screening day.</div></li><li class="half_rhythm"><div>Cells suspended in Sufu-KO-LIGHT assay medium to a density of 1.0 × 10<sup>6</sup> cells/mL</div></li><li class="half_rhythm"><div>5 μL/well cell suspension was dispensed to columns 3–48. 5 μL/well assay medium alone (without cells) was dispensed to columns 1–2 (positive control) in Corning white polystyrene tissue treated 1536 well assay plates (#3727) or Aurora® white polystyrene tissue treated 1536 well Low Base square well assay plates (#00029846) using Biotek Microflo Select peristaltic liquid handler/dispenser.</div></li><li class="half_rhythm"><div>Plates were centrifuged 1 min at 1000 rpm (200xG) on an Eppendorf 5810 centrifuge</div></li><li class="half_rhythm"><div>Plates were covered with Kalypsys brand stainless steel assay plate lids and placed over night (16–18 hrs) in humidified Liconic brand automated tissue culture incubator. Plates were stacked vertically in towers which rotate intermittently within the incubator at 37°C, 5% CO<sub>2</sub>.</div></li></ol></div><div id="ml340.s42"><h5>Day 2</h5><ol><li class="half_rhythm"><div>Kalypsys stainless steel lids were removed and 2.5 nL MLSMR test agents at 10 mM in DMSO stored in Labcyte Echo compatible Corning 1536 well Cyclic Olefin Copolymer (COC) plates were applied to assay wells (columns 5–48) using a Labcyte Echo 550 acoustic liquid handling system. Final assay concentration of test agents in the assay was 5 μM. 2.5 nL DMSO controls were also added to control wells (columns 1–4). Final DMSO concentration in the assay was 0.05%.</div></li><li class="half_rhythm"><div>Plates were centrifuged 1 min at 1000 rpm (200xG) on an Eppendorf 5810 centrifuge</div></li><li class="half_rhythm"><div>Plates were covered with Kalypsys brand stainless steel assay plate lids and place over night (16–18 hrs) in humidity controlled Liconic Automated tissue culture incubator. Incubator stacks plates vertically in towers at 37°C, 5% CO<sub>2</sub>.</div></li></ol></div><div id="ml340.s43"><h5>Day 3</h5><ol><li class="half_rhythm"><div>Kalypsys stainless steel lids were removed and replaced with plastic assay plate lids from Corning 1536 well assay plates (#3727) and plates returned to incubator.</div></li><li class="half_rhythm"><div>3 μL /well Bright-Glo luciferase detection reagent (Promega) was added to assay wells using Multidrop Combi liquid handler (Thermo) and immediately centrifuged for 30 seconds on a VSpin integrated microplate centrifuge at 1500 rpm (Velocity11/Agilent Technologies) and incubated for 10 minutes uncovered at room temperature. NB: plastic assay lids were removed by the HRB robotic system before addition of Bright-Glo and NOT replaced. Luminescence was read on a Viewlux microplate imager (PerkinElmer). Read time: 300 seconds, Binning: 4X.</div></li></ol><p>Please refer to PubChem AIDs Listed in <a class="figpopup" href="/books/NBK158949/table/ml340.t3/?report=objectonly" target="object" rid-figpopup="figml340t3" rid-ob="figobml340t3">Table 3</a> on the PubChem website (<a href="http://pubchem.ncbi.nlm.nih.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">http://pubchem.ncbi.nlm.nih.gov/</a>) for detailed protocols for all primary and secondary assays.</p></div></div></div></div><div id="ml340.s44"><h3>6.2. Chemistry: <sup>1</sup>H NMR, <sup>13</sup>C NMR, and LC-MS spectra of ML340</h3><div id="ml340.fu6" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=1H%20NMR%20Spectrum%20of%20ML340%20(400%20MHz%2C%20CDCl3).&p=BOOKS&id=158949_ml340fu24.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 src="/books/NBK158949/bin/ml340fu24.jpg" alt="1H NMR Spectrum of ML340 (400 MHz, CDCl3)." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="title"><sup>1</sup>H NMR Spectrum of <b>ML340</b> (400 MHz, CDCl<sub>3</sub>)</span></h3></div><div id="ml340.fu7" class="figure bk_fig"><div class="graphic"><img src="/books/NBK158949/bin/ml340fu25.jpg" alt="13C NMR Spectrum of ML340 (400 MHz, CDCl3)." /></div><h3><span class="title"><sup>13</sup>C NMR Spectrum of <b>ML340</b> (400 MHz, CDCl<sub>3</sub>)</span></h3></div><div id="ml340.fu8" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=LC-MS%20for%20ML340.&p=BOOKS&id=158949_ml340fu26.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 src="/books/NBK158949/bin/ml340fu26.jpg" alt="LC-MS for ML340." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="title">LC-MS for ML340</span></h3><div class="caption"><p>(Reverse phase Acquity UPLC HSS T3 C18 column)</p></div></div></div></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK158949_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><p class="contrib-group"><h4>Authors</h4><span itemprop="author">Robert Ardecky</span>,<sup>1</sup> <span itemprop="author">Gavin K. Magnuson</span>,<sup>1</sup> <span itemprop="author">Jiwen Zou</span>,<sup>1</sup> <span itemprop="author">Santhi R. Ganji</span>,<sup>1</sup> <span itemprop="author">Brock Brown</span>,<sup>1</sup> <span itemprop="author">Tram Ngo</span>,<sup>1</sup> <span itemprop="author">Julia Lee</span>,<sup>1</sup> <span itemprop="author">Fu-Yue Zeng</span>,<sup>1</sup> <span itemprop="author">Qing Sun</span>,<sup>1</sup> <span itemprop="author">Derek Stonich</span>,<sup>1</sup> <span itemprop="author">Sumeet Salaniwal</span>,<sup>1</sup> <span itemprop="author">Tomoyo Sakata</span>,<sup>3</sup> <span itemprop="author">Paul G. Rack</span>,<sup>3</sup> <span itemprop="author">Jennifer K. T. Casabar</span>,<sup>3</sup> <span itemprop="author">Arianna Mangravita-Novo</span>,<sup>2</sup> <span itemprop="author">Layton H. Smith</span>,<sup>2</sup> <span itemprop="author">Eduard Sergienko</span>,<sup>1</sup> <span itemprop="author">Thomas D.Y. Chung</span>,<sup>1</sup> <span itemprop="author">Anthony B. Pinkerton</span>,<sup>1</sup> <span itemprop="author">Ian Pass</span>,<sup>1</sup> and <span itemprop="author">James K. Chen</span><sup>3</sup>.<sup><img src="/corehtml/pmc/pmcgifs/corrauth.gif" alt="corresponding author" /></sup></p><h4>Affiliations</h4><div class="affiliation"><sup>1</sup>
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Sanford-Burnham Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA</div><div class="affiliation"><sup>2</sup>
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Sanford-Burnham Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, Orlando, Florida 32827, USA.</div><div class="affiliation"><sup>3</sup>
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Department of Chemical and Systems Biology, Stanford University, Stanford, California 94305, USA.</div><div class="affiliation"><sup><img src="/corehtml/pmc/pmcgifs/corrauth.gif" alt="corresponding author" /></sup>Corresponding author: Ian Pass, Ph.D.
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<span class="before-email-separator"></span><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="gro.mahnrubdrofnas@ssap.nai" class="oemail">gro.mahnrubdrofnas@ssap.nai</a></div><h3>Publication History</h3><p class="small">Received: <span itemprop="datePublished">December 17, 2012</span>; Last Update: <span itemprop="dateModified">May 13, 2014</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>Ardecky R, Magnuson GK, Zou J, et al. Small-molecule antagonists of Gli function. 2012 Dec 17 [Updated 2014 May 13]. 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/ml341/?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/ml339/?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="figobml340fu1"><div id="ml340.fu1" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK158949/bin/ml340fu1.jpg" alt="ML340." /></div><h3><span class="title">ML340</span></h3></div></article><article data-type="table-wrap" id="figobml340t1"><div id="ml340.t1" class="table"><h3><span class="label">Table 1</span><span class="title">Potency and selectivity characteristics for probes ML340</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK158949/table/ml340.t1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml340.t1_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml340.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CID/ML#</th><th id="hd_h_ml340.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Target Name</th><th id="hd_h_ml340.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">IC<sub>50</sub> (nM) [SID, AID]</th><th id="hd_h_ml340.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Anti-target Name(s)</th><th id="hd_h_ml340.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">IC<sub>50</sub> (μM) [SID, AID]</th><th id="hd_h_ml340.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Selectivity<br />Gli-Sufu/Wnt Signaling</th><th id="hd_h_ml340.t1_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Secondary Assay IC<sub>50</sub> (nM)<br />[SID, AID]</th></tr></thead><tbody><tr><td headers="hd_h_ml340.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CID 65389180<br /><a href="/pcsubstance/?term=ML340[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML340</a></td><td headers="hd_h_ml340.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Gli Antagonists (Sufu-KO-LIGHT)</td><td headers="hd_h_ml340.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">33.6 ± 4.3 (n=4)<br /><a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864401" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 150864401</a><br /><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/651836" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 651836</a> & <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/651837" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 651837</a></td><td headers="hd_h_ml340.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Wnt Signaling</td><td headers="hd_h_ml340.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">>21.8<br /><a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864401" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 150864401</a><br /><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/651882" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 651882</a></td><td headers="hd_h_ml340.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">64.9-fold</td><td headers="hd_h_ml340.t1_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr></tbody></table></div></div></article><article data-type="fig" id="figobml340f1"><div id="ml340.f1" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK158949/bin/ml340f1.jpg" alt="Fig. 1. The Hh pathway." /></div><h3><span class="label">Fig. 1</span><span class="title">The Hh pathway</span></h3><div class="caption"><p>Functional interactions between Hh signaling components and representative small-molecule inhibitors of the pathway are shown. Positive and negative regulatory proteins are depicted in green and red. respectively.</p></div></div></article><article data-type="fig" id="figobml340f2"><div id="ml340.f2" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK158949/bin/ml340f2.jpg" alt="Figure 2. Inhibition of Gli-Sufu-KO LIGHT reporter by HPI-1 and GDC-0449." /></div><h3><span class="label">Figure 2</span><span class="title">Inhibition of Gli-Sufu-KO LIGHT reporter by HPI-1 and GDC-0449</span></h3></div></article><article data-type="table-wrap" id="figobml340t2"><div id="ml340.t2" class="table"><h3><span class="label">Table 2</span><span class="title">Summary of Assays and AIDs</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK158949/table/ml340.t2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml340.t2_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml340.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">PubChemBioAssay Name</th><th id="hd_h_ml340.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">AIDs</th><th id="hd_h_ml340.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Probe Type</th><th id="hd_h_ml340.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Assay Type</th><th id="hd_h_ml340.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Assay Format</th><th id="hd_h_ml340.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Assay Detection & well format</th></tr></thead><tbody><tr><td headers="hd_h_ml340.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Summary assay for small molecule Antagonists of Gli-Sufu Antagonists [Summary]</td><td headers="hd_h_ml340.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588433" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">588433</a></td><td headers="hd_h_ml340.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Antagonist</td><td headers="hd_h_ml340.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Summary</td><td headers="hd_h_ml340.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Cell</td><td headers="hd_h_ml340.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Luminescence & 1536 well</td></tr><tr><td headers="hd_h_ml340.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">uHTS identification of Gli-Sufu Antagonists in a luminescence reporter assay [Primary]</td><td headers="hd_h_ml340.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588413" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">588413</a></td><td headers="hd_h_ml340.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Antagonist</td><td headers="hd_h_ml340.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Primary</td><td headers="hd_h_ml340.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Cell</td><td headers="hd_h_ml340.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Luminescence & 1536 well</td></tr><tr><td headers="hd_h_ml340.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Single concentration confirmation of uHTS antagonist hits from Gli-SUFU in a luminescent reporter assay [Confirmatory]</td><td headers="hd_h_ml340.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/602428" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">602428</a></td><td headers="hd_h_ml340.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Antagonist</td><td headers="hd_h_ml340.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Confirmatory (single conc triplicate)</td><td headers="hd_h_ml340.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Cell</td><td headers="hd_h_ml340.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Luminescence & 1536 well</td></tr><tr><td headers="hd_h_ml340.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dose response confirmation of uHTS antagonist hits from Gli-SUFU in a luminescent reporter assay [Confirmatory]</td><td headers="hd_h_ml340.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/602464" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">602464</a></td><td headers="hd_h_ml340.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Antagonist</td><td headers="hd_h_ml340.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Confirmatory (Dose Response)</td><td headers="hd_h_ml340.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Cell</td><td headers="hd_h_ml340.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Luminescence & 1536 well</td></tr><tr><td headers="hd_h_ml340.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dose response validation of uHTS antagonist hits from Gli-SUFU in a luminescent cytotoxicity assay [Confirmatory]</td><td headers="hd_h_ml340.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/651569" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">651569</a></td><td headers="hd_h_ml340.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Antagonist</td><td headers="hd_h_ml340.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Confirmatory (Dose Response)</td><td headers="hd_h_ml340.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Cell</td><td headers="hd_h_ml340.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Luminescence & 1536 well</td></tr><tr><td headers="hd_h_ml340.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dose response validation of uHTS Gli-SUFU antagonist hits in a Wnt3a luminescent reporter assay [Confirmatory]</td><td headers="hd_h_ml340.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/651570" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">651570</a></td><td headers="hd_h_ml340.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Antagonist</td><td headers="hd_h_ml340.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Confirmatory (Dose Response)</td><td headers="hd_h_ml340.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Cell</td><td headers="hd_h_ml340.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Luminescence & 1536 well</td></tr><tr><td headers="hd_h_ml340.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SAR analysis of small molecule antagonists of Gli-SUFU in a luminescent reporter assay - Set 1</td><td headers="hd_h_ml340.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/651836" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">651836</a></td><td headers="hd_h_ml340.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Antagonist</td><td headers="hd_h_ml340.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Secondary (Dry Powder</td><td headers="hd_h_ml340.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Cell</td><td headers="hd_h_ml340.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Luminescence & 1536 well</td></tr><tr><td headers="hd_h_ml340.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SAR analysis of small molecule antagonists of Gli-SUFU in a luminescent reporter assay - Set 2</td><td headers="hd_h_ml340.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/651837" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">651837</a></td><td headers="hd_h_ml340.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Antagonist</td><td headers="hd_h_ml340.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Secondary (Dry Powder</td><td headers="hd_h_ml340.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Cell</td><td headers="hd_h_ml340.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Luminescence & 1536 well</td></tr><tr><td headers="hd_h_ml340.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SAR analysis of small molecule antagonists of Gli-SUFU in a luminescent cytotoxicity assay - Set 1</td><td headers="hd_h_ml340.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/651842" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">651842</a></td><td headers="hd_h_ml340.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Antagonist</td><td headers="hd_h_ml340.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Secondary (Dry Powder</td><td headers="hd_h_ml340.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Cell</td><td headers="hd_h_ml340.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Luminescence & 1536 well</td></tr><tr><td headers="hd_h_ml340.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SAR analysis of small molecule antagonists of Gli-SUFU in a luminescent cytotoxicity assay - Set 2</td><td headers="hd_h_ml340.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/651859" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">651859</a></td><td headers="hd_h_ml340.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Antagonist</td><td headers="hd_h_ml340.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Secondary (Dry Powder</td><td headers="hd_h_ml340.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Cell</td><td headers="hd_h_ml340.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Luminescence & 1536 well</td></tr><tr><td headers="hd_h_ml340.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SAR analysis of small molecule antagonists of Gli-SUFU in a Wnt3a luminescent reporter assay</td><td headers="hd_h_ml340.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/651882" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">651882</a></td><td headers="hd_h_ml340.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Antagonist</td><td headers="hd_h_ml340.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Secondary (Dry Powder</td><td headers="hd_h_ml340.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Cell</td><td headers="hd_h_ml340.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Luminescence & 1536 well</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobml340f3"><div id="ml340.f3" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK158949/bin/ml340f3.jpg" alt="Figure 3. Structure of ML340." /></div><h3><span class="label">Figure 3</span><span class="title">Structure of <b>ML340</b></span></h3></div></article><article data-type="table-wrap" id="figobml340t4"><div id="ml340.t4" class="table"><h3><span class="label">Table 4</span><span class="title">Probe and Analog Submissions to MLSMR (BioFocus DPI) for Gli-Sufu Antagonist <b>ML340</b></span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK158949/table/ml340.t4/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml340.t4_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml340.t4_1_1_1_1" colspan="8" rowspan="1" style="text-align:center;vertical-align:middle;">Probe - CID65389180</th></tr><tr><th headers="hd_h_ml340.t4_1_1_1_1" id="hd_h_ml340.t4_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Probe/Analog</th><th headers="hd_h_ml340.t4_1_1_1_1" id="hd_h_ml340.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS_ID (BCCG)</th><th headers="hd_h_ml340.t4_1_1_1_1" id="hd_h_ml340.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS_ID (MLSMR)</th><th headers="hd_h_ml340.t4_1_1_1_1" id="hd_h_ml340.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID</th><th headers="hd_h_ml340.t4_1_1_1_1" id="hd_h_ml340.t4_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SID</th><th headers="hd_h_ml340.t4_1_1_1_1" id="hd_h_ml340.t4_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Source (vendor or syn)</th><th headers="hd_h_ml340.t4_1_1_1_1" id="hd_h_ml340.t4_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Amt (mg)</th><th headers="hd_h_ml340.t4_1_1_1_1" id="hd_h_ml340.t4_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Date ordered/submitted</th></tr></thead><tbody><tr><td headers="hd_h_ml340.t4_1_1_1_1 hd_h_ml340.t4_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Probe <a href="/pcsubstance/?term=ML340[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML340</a></td><td headers="hd_h_ml340.t4_1_1_1_1 hd_h_ml340.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0472020.0001</td><td headers="hd_h_ml340.t4_1_1_1_1 hd_h_ml340.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS004711949</td><td headers="hd_h_ml340.t4_1_1_1_1 hd_h_ml340.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">65389180</td><td headers="hd_h_ml340.t4_1_1_1_1 hd_h_ml340.t4_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864401" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">150864401</a></td><td headers="hd_h_ml340.t4_1_1_1_1 hd_h_ml340.t4_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml340.t4_1_1_1_1 hd_h_ml340.t4_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">34</td><td headers="hd_h_ml340.t4_1_1_1_1 hd_h_ml340.t4_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">12/01/2012</td></tr><tr><td headers="hd_h_ml340.t4_1_1_1_1 hd_h_ml340.t4_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Analog 1</td><td headers="hd_h_ml340.t4_1_1_1_1 hd_h_ml340.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0472009.0001</td><td headers="hd_h_ml340.t4_1_1_1_1 hd_h_ml340.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS004711954</td><td headers="hd_h_ml340.t4_1_1_1_1 hd_h_ml340.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">65389176</td><td headers="hd_h_ml340.t4_1_1_1_1 hd_h_ml340.t4_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864390" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">150864390</a></td><td headers="hd_h_ml340.t4_1_1_1_1 hd_h_ml340.t4_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml340.t4_1_1_1_1 hd_h_ml340.t4_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">24.4</td><td headers="hd_h_ml340.t4_1_1_1_1 hd_h_ml340.t4_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">12/01/2012</td></tr><tr><td headers="hd_h_ml340.t4_1_1_1_1 hd_h_ml340.t4_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Analog 2</td><td headers="hd_h_ml340.t4_1_1_1_1 hd_h_ml340.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0472010.0001</td><td headers="hd_h_ml340.t4_1_1_1_1 hd_h_ml340.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS004711953</td><td headers="hd_h_ml340.t4_1_1_1_1 hd_h_ml340.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">65389148</td><td headers="hd_h_ml340.t4_1_1_1_1 hd_h_ml340.t4_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864391" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">150864391</a></td><td headers="hd_h_ml340.t4_1_1_1_1 hd_h_ml340.t4_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml340.t4_1_1_1_1 hd_h_ml340.t4_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">43.4</td><td headers="hd_h_ml340.t4_1_1_1_1 hd_h_ml340.t4_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">12/01/2012</td></tr><tr><td headers="hd_h_ml340.t4_1_1_1_1 hd_h_ml340.t4_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Analog 3</td><td headers="hd_h_ml340.t4_1_1_1_1 hd_h_ml340.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0472014.0001</td><td headers="hd_h_ml340.t4_1_1_1_1 hd_h_ml340.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS004711952</td><td headers="hd_h_ml340.t4_1_1_1_1 hd_h_ml340.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">711685</td><td headers="hd_h_ml340.t4_1_1_1_1 hd_h_ml340.t4_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864395" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">150864395</a></td><td headers="hd_h_ml340.t4_1_1_1_1 hd_h_ml340.t4_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml340.t4_1_1_1_1 hd_h_ml340.t4_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">22.1</td><td headers="hd_h_ml340.t4_1_1_1_1 hd_h_ml340.t4_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">12/01/2012</td></tr><tr><td headers="hd_h_ml340.t4_1_1_1_1 hd_h_ml340.t4_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Analog 4</td><td headers="hd_h_ml340.t4_1_1_1_1 hd_h_ml340.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0472017.0001</td><td headers="hd_h_ml340.t4_1_1_1_1 hd_h_ml340.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS004711951</td><td headers="hd_h_ml340.t4_1_1_1_1 hd_h_ml340.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">65389159</td><td headers="hd_h_ml340.t4_1_1_1_1 hd_h_ml340.t4_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864398" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">150864398</a></td><td headers="hd_h_ml340.t4_1_1_1_1 hd_h_ml340.t4_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml340.t4_1_1_1_1 hd_h_ml340.t4_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">23.2</td><td headers="hd_h_ml340.t4_1_1_1_1 hd_h_ml340.t4_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">12/01/2012</td></tr><tr><td headers="hd_h_ml340.t4_1_1_1_1 hd_h_ml340.t4_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Analog 5</td><td headers="hd_h_ml340.t4_1_1_1_1 hd_h_ml340.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0472075.0001</td><td headers="hd_h_ml340.t4_1_1_1_1 hd_h_ml340.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS004711950</td><td headers="hd_h_ml340.t4_1_1_1_1 hd_h_ml340.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">65389175</td><td headers="hd_h_ml340.t4_1_1_1_1 hd_h_ml340.t4_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864414" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">150864414</a></td><td headers="hd_h_ml340.t4_1_1_1_1 hd_h_ml340.t4_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml340.t4_1_1_1_1 hd_h_ml340.t4_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">73.3</td><td headers="hd_h_ml340.t4_1_1_1_1 hd_h_ml340.t4_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">12/01/2012</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobml340f4"><div id="ml340.f4" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%204.%20Stability%20of%20ML340%20in%20PBS%20at%20ambient%20temperature.&p=BOOKS&id=158949_ml340f4.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/NBK158949/bin/ml340f4.jpg" alt="Figure 4. Stability of ML340 in PBS at ambient temperature." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 4</span><span class="title">Stability of ML340 in PBS at ambient temperature</span></h3></div></article><article data-type="table-wrap" id="figobml340t7"><div id="ml340.t7" class="table"><h3><span class="label">Table 7</span><span class="title">Summary of <i>in vitro</i> ADME Properties of Gli-Sufu Antagonists Probe <b>CID6538918</b></span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK158949/table/ml340.t7/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml340.t7_lrgtbl__"><table class="no_margin"><thead><tr><th id="hd_h_ml340.t7_1_1_1_1" rowspan="2" colspan="1" headers="hd_h_ml340.t7_1_1_1_1" style="text-align:center;vertical-align:top;">Probe<br />Probe ML#<br />BCCG MLS-#</th><th id="hd_h_ml340.t7_1_1_1_2" rowspan="2" colspan="1" headers="hd_h_ml340.t7_1_1_1_2" style="text-align:center;vertical-align:top;">Aqueous<br />Solubility<br />(μg/mL)<sup>a</sup><br />(@ pH)</th><th id="hd_h_ml340.t7_1_1_1_3" rowspan="2" colspan="1" headers="hd_h_ml340.t7_1_1_1_3" style="text-align:center;vertical-align:top;">PAMPA<br />Pe<br />(x10<sup>−6</sup> cm/s)<sup>b</sup><br />(@ Donor pH)</th><th id="hd_h_ml340.t7_1_1_1_4" rowspan="2" colspan="1" headers="hd_h_ml340.t7_1_1_1_4" style="text-align:center;vertical-align:top;">BBB-PAMPA<br />Pe<br />(x10<sup>−6</sup> cm/s)<sup>c</sup></th><th id="hd_h_ml340.t7_1_1_1_5" colspan="2" rowspan="1" style="text-align:center;vertical-align:top;">Plasma Protein Binding (% Bound)</th><th id="hd_h_ml340.t7_1_1_1_6" rowspan="2" colspan="1" headers="hd_h_ml340.t7_1_1_1_6" style="text-align:center;vertical-align:top;">Plasma Stability<sup>d</sup><br />Human<br />Mouse/1:1<br />Plasma:PBS</th><th id="hd_h_ml340.t7_1_1_1_7" rowspan="2" colspan="1" headers="hd_h_ml340.t7_1_1_1_7" style="text-align:center;vertical-align:top;">Hepatic<br />Microsome<br />Stability<sup>e</sup><br />Human/Mouse</th><th id="hd_h_ml340.t7_1_1_1_8" rowspan="2" colspan="1" headers="hd_h_ml340.t7_1_1_1_8" style="text-align:center;vertical-align:top;">Hepatic<br />Toxicity<sup>f</sup><br />LC50 (μM)</th></tr><tr><th headers="hd_h_ml340.t7_1_1_1_5" id="hd_h_ml340.t7_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Human<br />1μM/10μM</th><th headers="hd_h_ml340.t7_1_1_1_5" id="hd_h_ml340.t7_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Mouse<br />1μM/10μM</th></tr></thead><tbody><tr><td headers="hd_h_ml340.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CID 6538918<br /><a href="/pcsubstance/?term=ML340[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML340</a><br />MLS-0472020</td><td headers="hd_h_ml340.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.84 (5.0)<br />0.62 (6.2)<br />0.72 (7.4)</td><td headers="hd_h_ml340.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">970 (5.0)<br />1826 (6.2)<br />1399 (7.4)</td><td headers="hd_h_ml340.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">51</td><td headers="hd_h_ml340.t7_1_1_1_5 hd_h_ml340.t7_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">99.40/99.35</td><td headers="hd_h_ml340.t7_1_1_1_5 hd_h_ml340.t7_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">98.61/98.15</td><td headers="hd_h_ml340.t7_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">85.04/39.59</td><td headers="hd_h_ml340.t7_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">18.31/1.74</td><td headers="hd_h_ml340.t7_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">> 50</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>a</dt><dd><div id="ml340.tfn1"><p class="no_margin">in aqueous buffer, pH’s 5.0/6.2/7.4</p></div></dd></dl><dl class="bkr_refwrap"><dt>b</dt><dd><div id="ml340.tfn2"><p class="no_margin">in aqueous buffer; Donor compartment pH’s 5.0/6.2/7.4; Acceptor compartment pH 7.4</p></div></dd></dl><dl class="bkr_refwrap"><dt>c</dt><dd><div id="ml340.tfn3"><p class="no_margin">% remaining at 3 hr</p></div></dd></dl><dl class="bkr_refwrap"><dt>d</dt><dd><div id="ml340.tfn4"><p class="no_margin">% remaining at 1 hr</p></div></dd></dl><dl class="bkr_refwrap"><dt>e</dt><dd><div id="ml340.tfn5"><p class="no_margin">human and mouse liver microsomes</p></div></dd></dl><dl class="bkr_refwrap"><dt>f</dt><dd><div id="ml340.tfn6"><p class="no_margin">towards Fa2N-4 immortalized human hepatocytes</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobml340t3"><div id="ml340.t3" class="table"><h3><span class="label">Table 3</span><span class="title">Calculated Properties for ML340 <b>(CID 6020222)</b></span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK158949/table/ml340.t3/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml340.t3_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml340.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Calculated Property</th><th id="hd_h_ml340.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">Value</th></tr></thead><tbody><tr><td headers="hd_h_ml340.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Molecular Weight [g/mol]</td><td headers="hd_h_ml340.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">296.3669 [g/mol]</td></tr><tr><td headers="hd_h_ml340.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Molecular Formula</td><td headers="hd_h_ml340.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">C<sub>17</sub>H<sub>20</sub>N<sub>4</sub>O</td></tr><tr><td headers="hd_h_ml340.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">AlogP</td><td headers="hd_h_ml340.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3.2450</td></tr><tr><td headers="hd_h_ml340.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H-Bond Donor</td><td headers="hd_h_ml340.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1</td></tr><tr><td headers="hd_h_ml340.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H-Bond Acceptor</td><td headers="hd_h_ml340.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">4</td></tr><tr><td headers="hd_h_ml340.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Rotatable Bond Count</td><td headers="hd_h_ml340.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3</td></tr><tr><td headers="hd_h_ml340.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Exact Mass</td><td headers="hd_h_ml340.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">296.163711</td></tr><tr><td headers="hd_h_ml340.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MonoIsotopic Mass</td><td headers="hd_h_ml340.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">296.163711</td></tr><tr><td headers="hd_h_ml340.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Topological Polar Surface Area</td><td headers="hd_h_ml340.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">58.1</td></tr><tr><td headers="hd_h_ml340.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Heavy Atom Count</td><td headers="hd_h_ml340.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">22</td></tr><tr><td headers="hd_h_ml340.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Formal Charge</td><td headers="hd_h_ml340.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml340.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Complexity</td><td headers="hd_h_ml340.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">362</td></tr><tr><td headers="hd_h_ml340.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Isotope Atom Count</td><td headers="hd_h_ml340.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml340.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Defined Atom StereoCenter Count</td><td headers="hd_h_ml340.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml340.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Undefined Atom StereoCenter Count</td><td headers="hd_h_ml340.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml340.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Defined Bond StereoCenter Count</td><td headers="hd_h_ml340.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml340.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Undefined Bond StereoCenter Count</td><td headers="hd_h_ml340.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml340.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Covalently-Bonded Unit Count</td><td headers="hd_h_ml340.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobml340f7"><div id="ml340.f7" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK158949/bin/ml340f7.jpg" alt="Scheme 1. Synthesis of ML340, conditions." /></div><h3><span class="label">Scheme 1</span><span class="title">Synthesis of ML340, conditions</span></h3><div class="caption"><p><b>a</b>. benzoyl chloride, DIPEA, DMAP, DCM, reflux, overnight (78%); <b>b</b>. 4-methylpiperidine, 80°C, 2 hours (60%).</p></div></div></article><article data-type="fig" id="figobml340fu2"><div id="ml340.fu2" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK158949/bin/ml340fu2.jpg" alt="2." /></div><h3><span class="title">2</span></h3></div></article><article data-type="fig" id="figobml340fu3"><div id="ml340.fu3" class="figure"><div class="graphic"><img data-src="/books/NBK158949/bin/ml340fu3.jpg" alt="Image ml340fu3" /></div></div></article><article data-type="fig" id="figobml340f5"><div id="ml340.f5" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK158949/bin/ml340f5.jpg" alt="Figure 5. Screening hit triage." /></div><h3><span class="label">Figure 5</span><span class="title">Screening hit triage</span></h3></div></article><article data-type="table-wrap" id="figobml340t5"><div id="ml340.t5" class="table"><h3><span class="label">Table 5</span><span class="title">Summary of Gli-antagonist (Sufu-KO-LIGHT) HTS Performance</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK158949/table/ml340.t5/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml340.t5_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml340.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Parameter</th><th id="hd_h_ml340.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">Value (± SEM)</th></tr></thead><tbody><tr><td headers="hd_h_ml340.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SD– Positive control</td><td headers="hd_h_ml340.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.46 ± 0.06</td></tr><tr><td headers="hd_h_ml340.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SD – Negative control</td><td headers="hd_h_ml340.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">7.92 ± 3.04</td></tr><tr><td headers="hd_h_ml340.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">S/B</td><td headers="hd_h_ml340.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">85.11 ± 6.18</td></tr><tr><td headers="hd_h_ml340.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Signal Window</td><td headers="hd_h_ml340.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">5.95 ± 3.39</td></tr><tr><td headers="hd_h_ml340.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">S/N</td><td headers="hd_h_ml340.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">239.82 ± 32.70</td></tr><tr><td headers="hd_h_ml340.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Z′</td><td headers="hd_h_ml340.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.748 ± 0.092</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobml340f6"><div id="ml340.f6" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK158949/bin/ml340f6.jpg" alt="Figure 6. Dose response curve for ML340 in the cell-based Gli antagonist (Sufu-KO-LIGHT) assay." /></div><h3><span class="label">Figure 6</span><span class="title">Dose response curve for ML340 in the cell-based Gli antagonist (Sufu-KO-LIGHT) assay</span></h3></div></article><article data-type="table-wrap" id="figobml340t6"><div id="ml340.t6" class="table"><h3><span class="label">Table 6</span><span class="title">SAR explorations of ML340</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK158949/table/ml340.t6/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml340.t6_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml340.t6_1_1_1_1" colspan="7" rowspan="2" headers="hd_h_ml340.t6_1_1_1_1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK158949/bin/ml340fu4.jpg" alt="Image ml340fu4.jpg" /></div><br /><sup>*</sup><i>P = compounds purchased from commercial sources</i><br /><i>CP = “cherry pick” of 10 mM DMSO from NIH MLSMR</i><br /><i>S = compound synthesized de novo by SBCCG</i></th><th id="hd_h_ml340.t6_1_1_1_2" colspan="2" rowspan="1" style="text-align:center;vertical-align:middle;">Antagonist Activity</th></tr><tr><th headers="hd_h_ml340.t6_1_1_1_2" id="hd_h_ml340.t6_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Gli Sufu(KO)<br />IC<sub>50</sub> (μM)</th><th headers="hd_h_ml340.t6_1_1_1_2" id="hd_h_ml340.t6_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Wnt3a<br />IC<sub>50</sub> (μM)</th></tr><tr><th headers="hd_h_ml340.t6_1_1_1_1" id="hd_h_ml340.t6_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Entry</th><th headers="hd_h_ml340.t6_1_1_1_1" id="hd_h_ml340.t6_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID</th><th headers="hd_h_ml340.t6_1_1_1_1" id="hd_h_ml340.t6_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SID</th><th headers="hd_h_ml340.t6_1_1_1_1" id="hd_h_ml340.t6_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SBI-ID</th><th headers="hd_h_ml340.t6_1_1_1_1" id="hd_h_ml340.t6_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P/S<sup>*</sup></th><th headers="hd_h_ml340.t6_1_1_1_1" id="hd_h_ml340.t6_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">R<sub>1</sub></th><th headers="hd_h_ml340.t6_1_1_1_1" id="hd_h_ml340.t6_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">R<sub>2</sub></th><th headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_1 hd_h_ml340.t6_1_1_2_2" id="hd_h_ml340.t6_1_1_3_8" colspan="2" rowspan="1" style="text-align:center;vertical-align:middle;"><i>(n = 1 unless otherwise indicated)</i></th></tr></thead><tbody><tr><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_1" rowspan="3" colspan="1" style="text-align:center;vertical-align:middle;"><b>1 screen hit</b></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_2" rowspan="3" colspan="1" style="text-align:center;vertical-align:middle;">1540596</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/24828228" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">24828228</a></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_4" rowspan="3" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0272575</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CP<sup>*</sup></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_6" rowspan="4" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK158949/bin/ml340fu5.jpg" alt="Image ml340fu5.jpg" /></div></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_7" rowspan="3" colspan="1" style="text-align:center;vertical-align:middle;">Ph</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_1 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.295</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_2 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>21.8</td></tr><tr><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864362" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">150864362</a></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_1 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.0565, 0.0229</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_2 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>21.8</td></tr><tr><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864363" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">150864363</a></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_1 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.0242</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_2 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>21.8</td></tr><tr><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>2</b></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2987826</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864364" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">150864364</a></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471724</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4-Cl-Ph</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_1 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>11.7</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_2 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>21.8</td></tr><tr><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>3</b></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">65389196</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864365" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">150864365</a></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471844</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK158949/bin/ml340fu6.jpg" alt="Image ml340fu6.jpg" /></div></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Ph</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_1 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>11.7</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_2 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>21.8</td></tr><tr><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>4</b></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">65389179</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864366" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">150864366</a></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471845</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NMe<sub>2</sub></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Ph</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_1 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>11.7</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_2 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>21.8</td></tr><tr><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>5</b></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">65389183</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864367" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">150864367</a></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471908</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NEt<sub>2</sub></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Ph(2-Me Pyrimidine)</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_1 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>11.7</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_2 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>21.8</td></tr><tr><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>6</b></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">65389178</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864368" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">150864368</a></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471909</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NEt<sub>2</sub></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Ph</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_1 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>11.7</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_2 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>21.8</td></tr><tr><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>7</b></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">65389182</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864369" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">150864369</a></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471910</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK158949/bin/ml340fu5.jpg" alt="Image ml340fu5.jpg" /></div></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2-F-Ph</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_1 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.176</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_2 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><0.0426</td></tr><tr><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>8</b></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">65389197</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864370" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">150864370</a></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471911</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK158949/bin/ml340fu6.jpg" alt="Image ml340fu6.jpg" /></div></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2-F-Ph</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_1 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>11.7</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_2 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.696</td></tr><tr><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>9</b></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">65389167</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864371" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">150864371</a></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471912</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NEt<sub>2</sub></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2-F-Ph</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_1 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.556</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_2 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.172</td></tr><tr><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>10</b></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">65389164</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864372" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">150864372</a></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471913</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK158949/bin/ml340fu5.jpg" alt="Image ml340fu5.jpg" /></div></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3-F-Ph</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_1 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>11.7</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_2 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>21.8</td></tr><tr><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>11</b></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6538919</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864373" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">150864373</a></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471914</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK158949/bin/ml340fu6.jpg" alt="Image ml340fu6.jpg" /></div></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3-F-Ph</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_1 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>11.7</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_2 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>21.8</td></tr><tr><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>12</b></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">65389194</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864374" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">150864374</a></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471915</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NMe<sub>2</sub></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3-F-Ph</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_1 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>11.7</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_2 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>21.8</td></tr><tr><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>13</b></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">65389149</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864375" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">150864375</a></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471916</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NEt<sub>2</sub></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3-F-Ph</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_1 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>11.7</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_2 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>21.8</td></tr><tr><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>14</b></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">65389188</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864376" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">150864376</a></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471920</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK158949/bin/ml340fu5.jpg" alt="Image ml340fu5.jpg" /></div></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Ph (2-Me-Pyrimidine)</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_1 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>11.7</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_2 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>21.8</td></tr><tr><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>15</b></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">65389199</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864377" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">150864377</a></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471921</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK158949/bin/ml340fu6.jpg" alt="Image ml340fu6.jpg" /></div></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Ph (2-Me-Pyrimidine)</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_1 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>11.7</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_2 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>21.8</td></tr><tr><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>16</b></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6538915</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864378" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">150864378</a></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471922</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NMe<sub>2</sub></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Ph (2-Me-Pyrimidine)</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_1 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>11.7</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_2 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>21.8</td></tr><tr><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>17</b></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">65389168</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864379" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">150864379</a></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471923</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK158949/bin/ml340fu7.jpg" alt="Image ml340fu7.jpg" /></div></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3-F-Ph</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_1 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>11.7</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_2 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>21.8</td></tr><tr><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>18</b></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">65389193</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864380" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">150864380</a></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471924</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK158949/bin/ml340fu5.jpg" alt="Image ml340fu5.jpg" /></div></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5-Br-Furan</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_1 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>11.7</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_2 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>21.8</td></tr><tr><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>19</b></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">65389156</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864381" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">150864381</a></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471925</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NEt<sub>2</sub></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5-Br-Furan</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_1 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>11.7</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_2 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>21.8</td></tr><tr><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>20</b></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">653892</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864382" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">150864382</a></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471926</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK158949/bin/ml340fu5.jpg" alt="Image ml340fu5.jpg" /></div></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3,5-di-OMe-Ph</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_1 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>11.7</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_2 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>21.8</td></tr><tr><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>21</b></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">65389158</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864383" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">150864383</a></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471934</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK158949/bin/ml340fu6.jpg" alt="Image ml340fu6.jpg" /></div></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3,5-di-OMe-Ph</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_1 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>11.7</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_2 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>21.8</td></tr><tr><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>22</b></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">65389153</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864384" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">150864384</a></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471935</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NMe<sub>2</sub></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3,5-di-OMe-Ph</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_1 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>11.7</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_2 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>21.8</td></tr><tr><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>23</b></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">65389157</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864385" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">150864385</a></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471936</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NEt<sub>2</sub></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3,5-di-OMe-Ph</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_1 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>11.7</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_2 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>21.8</td></tr><tr><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>24</b></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">65389202</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864386" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">150864386</a></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471937</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NH-Ph-2-Cl</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3,5-di-OMe-Ph</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_1 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>11.7</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_2 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>21.8</td></tr><tr><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>25</b></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">65389165</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864387" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">150864387</a></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471938</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NMe<sub>2</sub></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2-F-Ph</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_1 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>11.7</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_2 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>21.8</td></tr><tr><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>26</b></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">65389152</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864388" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">150864388</a></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471939</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NMe<sub>2</sub></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3-CN-Ph</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_1 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>11.7</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_2 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>21.8</td></tr><tr><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>27</b></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">65389162</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864389" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">150864389</a></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471940</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NEt<sub>2</sub></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3-CN-Ph</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_1 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>11.7</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_2 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>21.8</td></tr><tr><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>28</b></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">65389176</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864390" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">150864390</a></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0472009</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK158949/bin/ml340fu8.jpg" alt="Image ml340fu8.jpg" /></div></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Ph</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_1 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.0612 ± 0.0274 (n=3)</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_2 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>21.8</td></tr><tr><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>29</b></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">65389148</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864391" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">150864391</a></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0472010</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK158949/bin/ml340fu9.jpg" alt="Image ml340fu9.jpg" /></div></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Ph</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_1 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>11.7</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_2 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>21.8</td></tr><tr><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>30</b></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">65389184</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864392" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">150864392</a></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0472011</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK158949/bin/ml340fu10.jpg" alt="Image ml340fu10.jpg" /></div></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Ph</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_1 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>11.7</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_2 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>21.8</td></tr><tr><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>31</b></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">65389187</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864393" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">150864393</a></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0472012</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK158949/bin/ml340fu11.jpg" alt="Image ml340fu11.jpg" /></div></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Ph</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_1 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>11.7</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_2 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>21.8</td></tr><tr><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>32</b></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">65389155</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864394" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">150864394</a></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0472013</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK158949/bin/ml340fu12.jpg" alt="Image ml340fu12.jpg" /></div></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Ph</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_1 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>11.7</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_2 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>21.8</td></tr><tr><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>33</b></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">711685</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864395" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">150864395</a></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0472014</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK158949/bin/ml340fu13.jpg" alt="Image ml340fu13.jpg" /></div></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Ph</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_1 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>11.7</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_2 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>21.8</td></tr><tr><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>34</b></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6538916</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864396" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">150864396</a></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0472015</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK158949/bin/ml340fu14.jpg" alt="Image ml340fu14.jpg" /></div></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Ph</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_1 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>11.7</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_2 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>21.8</td></tr><tr><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>35</b></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">65389203</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864397" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">150864397</a></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0472016</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK158949/bin/ml340fu15.jpg" alt="Image ml340fu15.jpg" /></div></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Ph</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_1 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>11.7</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_2 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>21.8</td></tr><tr><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>36</b></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">65389159</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864398" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">150864398</a></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0472017</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK158949/bin/ml340fu16.jpg" alt="Image ml340fu16.jpg" /></div></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Ph</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_1 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>11.7</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_2 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>21.8</td></tr><tr><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>37</b></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">65389204</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864399" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">150864399</a></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0472018</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK158949/bin/ml340fu17.jpg" alt="Image ml340fu17.jpg" /></div></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Ph</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_1 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>11.7</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_2 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>21.8</td></tr><tr><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>38</b></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6538917</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864400" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">150864400</a></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0472019</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK158949/bin/ml340fu7.jpg" alt="Image ml340fu7.jpg" /></div></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Ph</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_1 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>11.7</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_2 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>21.8</td></tr><tr><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>39</b><br /><a href="/pcsubstance/?term=ML340[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML340</a></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6538918</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864401" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">150864401</a></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0472020</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK158949/bin/ml340fu18.jpg" alt="Image ml340fu18.jpg" /></div></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Ph</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_1 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.0336 ± 0.0043 (n=4)</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_2 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>21.8</td></tr><tr><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>40</b></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6538917</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864402" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">150864402</a></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0472032</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK158949/bin/ml340fu19.jpg" alt="Image ml340fu19.jpg" /></div></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Ph</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_1 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>11.7</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_2 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>21.8</td></tr><tr><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>41</b></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">65389172</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864403" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">150864403</a></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0472033</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK158949/bin/ml340fu20.jpg" alt="Image ml340fu20.jpg" /></div></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Ph</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_1 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>11.7</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_2 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>21.8</td></tr><tr><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>42</b></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">65389185</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864404" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">150864404</a></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0472034</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK158949/bin/ml340fu21.jpg" alt="Image ml340fu21.jpg" /></div></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Ph</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_1 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>11.7</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_2 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>21.8</td></tr><tr><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>43</b></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">65389166</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864405" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">150864405</a></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0472035</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_6" rowspan="14" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK158949/bin/ml340fu5.jpg" alt="Image ml340fu5.jpg" /></div></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4-CN-Ph</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_1 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>11.7</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_2 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>21.8</td></tr><tr><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>44</b></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">66563705</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/152199733" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">152199733</a></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0472036</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4-CF<sub>3</sub>-Ph</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_1 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>11.7</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_2 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>21.8</td></tr><tr><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>45</b></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">66563706</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/152199734" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">152199734</a></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0472037</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3-CF<sub>3</sub>-Ph</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_1 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>11.7</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_2 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6.48</td></tr><tr><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>46</b></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">65389171</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864406" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">150864406</a></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0472049</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2-Cl-Ph</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_1 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>11.7</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_2 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>21.8</td></tr><tr><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>47</b></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">65389173</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864407" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">150864407</a></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0472050</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2-OMe-Ph</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_1 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>11.7</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_2 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>21.8</td></tr><tr><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>48</b></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">65389154</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864408" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">150864408</a></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0472051</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3-OMe-Ph</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_1 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>11.7</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_2 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>21.8</td></tr><tr><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>49</b></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2987826</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864409" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">150864409</a></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0472052</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4-Cl-Ph</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_1 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>11.7</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_2 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>21.8</td></tr><tr><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>50</b></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">65389186</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864410" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">150864410</a></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0472053</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4-Me-Ph</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_1 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>9.7</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_2 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>21.8</td></tr><tr><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>51</b></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">65389181</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864411" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">150864411</a></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0472054</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2-Furan</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_1 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>11.7</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_2 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>21.8</td></tr><tr><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>52</b></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">65389191</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864412" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">150864412</a></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0472055</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3-CN-Ph</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_1 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>11.7</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_2 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>21.8</td></tr><tr><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>53</b></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">65389192</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864413" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">150864413</a></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0472074</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2-benzothiophene</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_1 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>11.7</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_2 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>21.8</td></tr><tr><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>54</b></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">65389175</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864414" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">150864414</a></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0472075</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2-Thiophene</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_1 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>11.7</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_2 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>21.8</td></tr><tr><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>55</b></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">65389201</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864415" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">150864415</a></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0472076</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3-Thiophene</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_1 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>11.7</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_2 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>21.8</td></tr><tr><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>56</b></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">65389161</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/150864416" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">150864416</a></td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0472081</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml340.t6_1_1_1_1 hd_h_ml340.t6_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1-Naphthyl</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_1 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>11.7</td><td headers="hd_h_ml340.t6_1_1_1_2 hd_h_ml340.t6_1_1_2_2 hd_h_ml340.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>21.8</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobml340fu4"><div id="ml340.fu4" class="figure"><div class="graphic"><img data-src="/books/NBK158949/bin/ml340fu22.jpg" alt="Image ml340fu22" /></div></div></article><article data-type="fig" id="figobml340fu5"><div id="ml340.fu5" class="figure"><div class="graphic"><img data-src="/books/NBK158949/bin/ml340fu23.jpg" alt="Image ml340fu23" /></div></div></article><article data-type="fig" id="figobml340fu6"><div id="ml340.fu6" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=1H%20NMR%20Spectrum%20of%20ML340%20(400%20MHz%2C%20CDCl3).&p=BOOKS&id=158949_ml340fu24.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/NBK158949/bin/ml340fu24.jpg" alt="1H NMR Spectrum of ML340 (400 MHz, CDCl3)." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="title"><sup>1</sup>H NMR Spectrum of <b>ML340</b> (400 MHz, CDCl<sub>3</sub>)</span></h3></div></article><article data-type="fig" id="figobml340fu7"><div id="ml340.fu7" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK158949/bin/ml340fu25.jpg" alt="13C NMR Spectrum of ML340 (400 MHz, CDCl3)." /></div><h3><span class="title"><sup>13</sup>C NMR Spectrum of <b>ML340</b> (400 MHz, CDCl<sub>3</sub>)</span></h3></div></article><article data-type="fig" id="figobml340fu8"><div id="ml340.fu8" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=LC-MS%20for%20ML340.&p=BOOKS&id=158949_ml340fu26.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/NBK158949/bin/ml340fu26.jpg" alt="LC-MS for ML340." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="title">LC-MS for ML340</span></h3><div class="caption"><p>(Reverse phase Acquity UPLC HSS T3 C18 column)</p></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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