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<meta name="robots" content="INDEX,FOLLOW,NOARCHIVE" /><meta name="citation_inbook_title" content="Probe Reports from the NIH Molecular Libraries Program [Internet]" /><meta name="citation_title" content="Probe Report for RBBP9 Inhibitors - Probe 2" /><meta name="citation_publisher" content="National Center for Biotechnology Information (US)" /><meta name="citation_date" content="2010/10/20" /><meta name="citation_author" content="DA Bachovchin" /><meta name="citation_author" content="AE Speers" /><meta name="citation_author" content="SJ Brown" /><meta name="citation_author" content="BF Cravatt" /><meta name="citation_author" content="V, Fernandez-Vega" /><meta name="citation_author" content="T Spicer" /><meta name="citation_author" content="BA Mercer" /><meta name="citation_author" content="J Ferguson" /><meta name="citation_author" content="P Hodder" /><meta name="citation_author" content="HR Rosen" /><meta name="citation_pmid" content="21433382" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK50690/" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="Probe Report for RBBP9 Inhibitors - Probe 2" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="National Center for Biotechnology Information (US)" /><meta name="DC.Contributor" content="DA Bachovchin" /><meta name="DC.Contributor" content="AE Speers" /><meta name="DC.Contributor" content="SJ Brown" /><meta name="DC.Contributor" content="BF Cravatt" /><meta name="DC.Contributor" content="V, Fernandez-Vega" /><meta name="DC.Contributor" content="T Spicer" /><meta name="DC.Contributor" content="BA Mercer" /><meta name="DC.Contributor" content="J Ferguson" /><meta name="DC.Contributor" content="P Hodder" /><meta name="DC.Contributor" content="HR Rosen" /><meta name="DC.Date" content="2010/10/20" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK50690/" /><meta name="description" content="The retinoblastoma (RB) tumor suppressor protein controls cell cycle progression by regulating the activity of the transcription factor E2F, which activates genes essential for DNA replication. Thus, factors that bind and regulate RB activity are considered valuable targets for preventing tumorigenesis. The enzyme RB binding protein 9 (RBBP9) is widely expressed in different tissues and upregulated in certain tumors. As a result, the identification of compounds that selectively inhibit RBBP9 activity would serve as potentially valuable probes for the study of apoptosis, cell cycle, and tumorigenesis. We previously reported a modestly potent, RBBP9 reversible inhibitor, ML081 (CID-6603320). However, ML081 exhibits high cytotoxicity. We, therefore, have now identified a newer probe, ML114 (CID-5934766), which is 10-fold more potent than ML081, exhibits no cytotoxicity, and is from an entirely different structural and mechanistic class of compounds that covalently inhibit RBBP9. This new probe will be useful for in vitro assays in which it is desirable to specifically block RBBP9 activity for primary research purposes." /><meta name="og:title" content="Probe Report for RBBP9 Inhibitors - Probe 2" /><meta name="og:type" content="book" /><meta name="og:description" content="The retinoblastoma (RB) tumor suppressor protein controls cell cycle progression by regulating the activity of the transcription factor E2F, which activates genes essential for DNA replication. Thus, factors that bind and regulate RB activity are considered valuable targets for preventing tumorigenesis. The enzyme RB binding protein 9 (RBBP9) is widely expressed in different tissues and upregulated in certain tumors. As a result, the identification of compounds that selectively inhibit RBBP9 activity would serve as potentially valuable probes for the study of apoptosis, cell cycle, and tumorigenesis. We previously reported a modestly potent, RBBP9 reversible inhibitor, ML081 (CID-6603320). However, ML081 exhibits high cytotoxicity. We, therefore, have now identified a newer probe, ML114 (CID-5934766), which is 10-fold more potent than ML081, exhibits no cytotoxicity, and is from an entirely different structural and mechanistic class of compounds that covalently inhibit RBBP9. 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<div class="pre-content"><div><div class="bk_prnt"><p class="small">NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.</p><p>Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010-. </p></div><div class="iconblock clearfix whole_rhythm no_top_margin bk_noprnt"><a class="img_link icnblk_img" title="Table of Contents Page" href="/books/n/mlprobe/"><img class="source-thumb" src="/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-mlprobe-lrg.png" alt="Cover of Probe Reports from the NIH Molecular Libraries Program" height="100px" width="80px" /></a><div class="icnblk_cntnt eight_col"><h2>Probe Reports from the NIH Molecular Libraries Program [Internet].</h2><a data-jig="ncbitoggler" href="#__NBK50690_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK50690_dtls__"><div>Bethesda (MD): National Center for Biotechnology Information (US); 2010-.</div></div><div class="half_rhythm"><ul class="inline_list"><li style="margin-right:1em"><a class="bk_cntns" href="/books/n/mlprobe/">Contents</a></li></ul></div><div class="bk_noprnt"><form method="get" action="/books/n/mlprobe/" id="bk_srch"><div class="bk_search"><label for="bk_term" class="offscreen_noflow">Search term</label><input type="text" title="Search this book" id="bk_term" name="term" value="" data-jig="ncbiclearbutton" /> <input type="submit" class="jig-ncbibutton" value="Search this book" submit="false" style="padding: 0.1em 0.4em;" /></div></form></div></div><div class="icnblk_cntnt two_col"><div class="pagination bk_noprnt"><a class="active page_link prev" href="/books/n/mlprobe/ml115/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/mlprobe/ml113/" title="Next page in this title">Next ></a></div></div></div></div></div>
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<div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><h1 id="_NBK50690_"><span class="title" itemprop="name">Probe Report for RBBP9 Inhibitors - Probe 2</span></h1><p class="contrib-group"><span itemprop="author">DA Bachovchin</span>, <span itemprop="author">AE Speers</span>, <span itemprop="author">SJ Brown</span>, <span itemprop="author">BF Cravatt</span>, <span itemprop="author">V, Fernandez-Vega</span>, <span itemprop="author">T Spicer</span>, <span itemprop="author">BA Mercer</span>, <span itemprop="author">J Ferguson</span>, <span itemprop="author">P Hodder</span>, and <span itemprop="author">HR Rosen</span>.</p><p class="small">Received: <span itemprop="datePublished">August 20, 2009</span>; Last Update: <span itemprop="dateModified">October 20, 2010</span>.</p></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="_abs_rndgid_" itemprop="description"><p>The retinoblastoma (RB) tumor suppressor protein controls cell cycle progression by regulating the activity of the transcription factor E2F, which activates genes essential for DNA replication. Thus, factors that bind and regulate RB activity are considered valuable targets for preventing tumorigenesis. The enzyme RB binding protein 9 (RBBP9) is widely expressed in different tissues and upregulated in certain tumors. As a result, the identification of compounds that selectively inhibit RBBP9 activity would serve as potentially valuable probes for the study of apoptosis, cell cycle, and tumorigenesis. We previously reported a modestly potent, RBBP9 reversible inhibitor, ML081 (CID-6603320). However, ML081 exhibits high cytotoxicity. We, therefore, have now identified a newer probe, ML114 (CID-5934766), which is 10-fold more potent than ML081, exhibits no cytotoxicity, and is from an entirely different structural and mechanistic class of compounds that covalently inhibit RBBP9. This new probe will be useful for in vitro assays in which it is desirable to specifically block RBBP9 activity for primary research purposes.</p></div><div class="h2"></div><p><b>Assigned Assay Grant #:</b> R01 CA087660-05</p><p><b>Screening Center Name & PI:</b> Scripps Research Institute Molecular Screening Center (SRIMSC), H. Rosen</p><p><b>Chemistry Center Name & PI:</b> SRIMSC, H. Rosen</p><p><b>Assay Submitter & Institution:</b> Ben Cravatt, TSRI</p><p><b>PubChem Summary Bioassay Identifier (AID):</b>
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<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1790" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1790</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2299" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2299</a></p><div id="ml114.fu1" class="figure"><div class="graphic"><img src="/books/NBK50690/bin/ml114fu1.jpg" alt="Image ml114fu1" /></div></div><div id="ml114.tu1" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK50690/table/ml114.tu1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml114.tu1_lrgtbl__"><table><tbody><tr><td colspan="2" rowspan="1" style="text-align:center;vertical-align:top;">RBBP9 Inhibitor Probe</td></tr><tr><td colspan="2" rowspan="1" style="text-align:center;vertical-align:top;">(Oxime Ester Scaffold)</td></tr><tr><td rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CID: 5934766</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">SID: 85098567</td></tr><tr><td colspan="2" rowspan="1" style="text-align:center;vertical-align:top;">MLS: MLS002473500</td></tr><tr><td colspan="2" rowspan="1" style="text-align:center;vertical-align:top;">RBBP9 IC50: 0.63 μM</td></tr><tr><td colspan="2" rowspan="1" style="text-align:center;vertical-align:top;">Anti-Target (other serine hydrolases) IC50: >100 μM</td></tr><tr><td colspan="2" rowspan="1" style="text-align:center;vertical-align:top;">Cytox CC50: >100 μM</td></tr><tr><td colspan="2" rowspan="1" style="text-align:center;vertical-align:top;"><a href="/pcsubstance/?term=ML114[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML114</a></td></tr></tbody></table></div></div><div id="ml114.s2"><h2 id="_ml114_s2_">Probe Structure & Characteristics and Prior Art</h2><p>As described in the CPDP, the chief goal for this probe development project was to find a
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selective inhibitor of the retinoblastoma binding protein 9 (RBBP9). In collaboration with the
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SRIMSC, we previously reported a modestly potent 8 µM reversible inhibitor that was selective RBBP9
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(emetine, CID 6603320, <a href="https://pubchem.ncbi.nlm.nih.gov/substance/855836" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-855836</a>). However, emetine exhibited high cytotoxicity (CC50 < 100 nM,
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see <a class="figpopup" href="/books/NBK50690/figure/ml114.f2/?report=objectonly" target="object" rid-figpopup="figml114f2" rid-ob="figobml114f2">Figure A2.2</a>
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<a href="#ml114.s32">Appendix 2</a>). As such, we optimized a second scaffold from the uHTS screening hits to achieve greater potency towards RBBP9 and reduced cytotoxicity. The probe (<a href="/pcsubstance/?term=ML114[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML114</a>) detailed in this report is 10-fold more potent than emetine (IC50 0.63µM), exhibits no cytotoxicity up to 100 µM concentration, and is from an entirely different structural and mechanistic class of inhibitors. Unlike emetine, <a href="/pcsubstance/?term=ML114[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML114</a> covalently inhibits RBBP9. This probe is highly selective (>100-fold), as demonstrated by lack of serine-hydrolase anti-targets by competitive activity-based protein profiling (ABPP) assays. No other selective RBBP9 inhibitors have been reported to date.</p><p>Please see the <a class="figpopup" href="/books/NBK50690/table/ml114.tu2/?report=objectonly" target="object" rid-figpopup="figml114tu2" rid-ob="figobml114tu2">probe table</a> on the next page for all results described above.</p></div><div id="ml114.s3"><h2 id="_ml114_s3_">Probe Selection</h2><p>Following the uHTS campaign and counterscreening by gel-based competitive activity-based protein
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profiling (ABPP) in proteomes, an oxime ester class of inhibitor was identified for probe
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development. Following two rounds of SAR, <a href="/pcsubstance/?term=ML114[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML114</a> (Compound <b>1</b>, <a class="figpopup" href="/books/NBK50690/table/ml114.t2/?report=objectonly" target="object" rid-figpopup="figml114t2" rid-ob="figobml114t2">Table A2.1</a>
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<a href="#ml114.s32">Appendix 2</a>) was selected as a probe, as it was the most potent
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and selective analog and exhibited no cytotoxicity up to 100 µM. <a href="/pcsubstance/?term=ML114[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML114</a> is ~3-fold more potent than
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the top initial hit (compound <b>2</b>, <a class="figpopup" href="/books/NBK50690/table/ml114.t2/?report=objectonly" target="object" rid-figpopup="figml114t2" rid-ob="figobml114t2">Table A2.1</a>
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<a href="#ml114.s32">Appendix 2</a>).</p></div><div id="ml114.s4"><h2 id="_ml114_s4_">Recommendations for the Scientific Use of This Probe</h2><p>This compound is useful for in vitro assays in which it is desirable to specifically block RBBP9 activity for primary research purposes.</p></div><div id="ml114.s5"><h2 id="_ml114_s5_">1. Scientific Rationale for Project</h2><p>The retinoblastoma (RB) tumor suppressor protein controls cell cycle progression by regulating the activity of the transcription factor E2F (<a class="bk_pop" href="#ml114.r1">1</a>), which activates genes essential for DNA replication. Due to the critical role of RB in regulating the cell cycle, factors that bind and regulate RB activity are considered valuable targets for preventing tumorigenesis. One such protein, RB binding protein 9 (RBBP9), is widely expressed in different tissues and upregulated in certain tumors (<a class="bk_pop" href="#ml114.r2">2</a>, <a class="bk_pop" href="#ml114.r3">3</a>). The RBBP9 protein contains an alpha/beta hydrolase fold, which belongs to the DUF1234 domain superfamily of unknown function. Although an enzymatic activity for RBBP9 has not been reported, this protein does react with activity-based probes that target serine hydrolases, suggesting that it is a functional enzyme. Also consistent with this premise, the crystal structure of RBBP9 was recently solved and revealed a well-structured active site with a properly arranged catalytic triad indicative of serine hydrolase activity (<a class="bk_pop" href="#ml114.r4">4</a>). A role for RBBP9 in cellular transformation is supported by studies showing that RBBP9 mRNA expression is increased in transformed rat liver cell lines and human liver tumor biopsies (<a class="bk_pop" href="#ml114.r3">3</a>). Furthermore, RBBP9-overexpressing cells form tumors when implanted into immuno-deficient mice (<a class="bk_pop" href="#ml114.r3">3</a>), and RBBP9 overexpression confers resistance to TGF-β1-induced growth inhibition through its interaction with RB and displacement of E2F (<a class="bk_pop" href="#ml114.r3">3</a>, <a class="bk_pop" href="#ml114.r5">5</a>). RBBP9 is also suggested to play a role in gender-related differential responses to radiation-induced cell proliferation (<a class="bk_pop" href="#ml114.r6">6</a>). As a result, the identification of compounds that selectively inhibit RBBP9 activity may provide valuable probes for the study of apoptosis, cell cycle, and tumorigenesis.</p><p>As a serine hydrolase, catalytically active RBBP9 is readily labeled by fluorescent activity-based protein profiling (ABPP) probes bearing a fluorophosphonate (FP) reactive group (<a class="bk_pop" href="#ml114.r7">7</a>). This reactivity can be exploited for inhibitor discovery using a competitive-ABPP platform, whereby small molecule enzyme inhibition is assessed by the ability to out-compete ABPP probe labeling (<a class="bk_pop" href="#ml114.r8">8</a>). When used in the context of a complex proteome, competitive-ABPP also offers a means to assess inhibitor selectivity against a wide range of probe-reactive enzymes. Competitive-ABPP has been configured to operate in a high-throughput manner via fluorescence polarization readout, FluoPol-ABPP (<a class="bk_pop" href="#ml114.r9">9</a>). Given the lack of substrate assays for RBBP9, the FluoPol-ABPP platform offers a unique opportunity to develop inhibitors for this important enzyme.</p><div id="ml114.tu2" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK50690/table/ml114.tu2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml114.tu2_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_ml114.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Probe or Analog (# in SAR Table)</th><th id="hd_h_ml114.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID/ML</th><th id="hd_h_ml114.tu2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SID</th><th id="hd_h_ml114.tu2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS</th><th id="hd_h_ml114.tu2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Target Name</th><th id="hd_h_ml114.tu2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Target IC<sub>50</sub> [<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2254" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2254</a>] (μM)</th><th id="hd_h_ml114.tu2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Anti-target Name</th><th id="hd_h_ml114.tu2_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Anti-Target IC<sub>50</sub> [<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2254" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2254</a>] (μM)</th><th id="hd_h_ml114.tu2_1_1_1_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Selectivity</th><th id="hd_h_ml114.tu2_1_1_1_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Secondary Assay Cytox CC<sub>50</sub> [<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2243" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2243</a>] (nM)</th></tr></thead><tbody><tr><td headers="hd_h_ml114.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>Probe (1)</b></td><td headers="hd_h_ml114.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5934766/<a href="/pcsubstance/?term=ML114[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML114</a></td><td headers="hd_h_ml114.tu2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85098567" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85098567</a></td><td headers="hd_h_ml114.tu2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS002473500</td><td headers="hd_h_ml114.tu2_1_1_1_5" rowspan="1" colspan="1" style="background-color:#CCFFFF;text-align:center;vertical-align:middle;">RBBP9</td><td headers="hd_h_ml114.tu2_1_1_1_6" rowspan="1" colspan="1" style="background-color:#CCFFFF;text-align:center;vertical-align:middle;">0.63</td><td headers="hd_h_ml114.tu2_1_1_1_7" rowspan="1" colspan="1" style="background-color:#CCFFCC;text-align:center;vertical-align:middle;">>30 serine hydrolases(SHs)</td><td headers="hd_h_ml114.tu2_1_1_1_8" rowspan="1" colspan="1" style="background-color:#CCFFCC;text-align:center;vertical-align:middle;">>100</td><td headers="hd_h_ml114.tu2_1_1_1_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>100-fold</td><td headers="hd_h_ml114.tu2_1_1_1_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>100000</td></tr><tr><td headers="hd_h_ml114.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>Analog 1 (2)</b></td><td headers="hd_h_ml114.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5524575</td><td headers="hd_h_ml114.tu2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85098568" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85098568</a></td><td headers="hd_h_ml114.tu2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS002473501</td><td headers="hd_h_ml114.tu2_1_1_1_5" rowspan="1" colspan="1" style="background-color:#CCFFFF;text-align:center;vertical-align:middle;">RBBP9</td><td headers="hd_h_ml114.tu2_1_1_1_6" rowspan="1" colspan="1" style="background-color:#CCFFFF;text-align:center;vertical-align:middle;">1.9</td><td headers="hd_h_ml114.tu2_1_1_1_7" rowspan="1" colspan="1" style="background-color:#CCFFCC;text-align:center;vertical-align:middle;">>30 SHs</td><td headers="hd_h_ml114.tu2_1_1_1_8" rowspan="1" colspan="1" style="background-color:#CCFFCC;text-align:center;vertical-align:middle;">100 75-kDa SH, >100 all other SHs</td><td headers="hd_h_ml114.tu2_1_1_1_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">50-fold</td><td headers="hd_h_ml114.tu2_1_1_1_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NT<sup><a class="bk_pop" href="#ml114.tfn1">*</a></sup></td></tr><tr><td headers="hd_h_ml114.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>Analog 2 (3)</b></td><td headers="hd_h_ml114.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5823053</td><td headers="hd_h_ml114.tu2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85098569" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85098569</a></td><td headers="hd_h_ml114.tu2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS002473502</td><td headers="hd_h_ml114.tu2_1_1_1_5" rowspan="1" colspan="1" style="background-color:#CCFFFF;text-align:center;vertical-align:middle;">RBBP9</td><td headers="hd_h_ml114.tu2_1_1_1_6" rowspan="1" colspan="1" style="background-color:#CCFFFF;text-align:center;vertical-align:middle;">5.7</td><td headers="hd_h_ml114.tu2_1_1_1_7" rowspan="1" colspan="1" style="background-color:#CCFFCC;text-align:center;vertical-align:middle;">>30 SHs</td><td headers="hd_h_ml114.tu2_1_1_1_8" rowspan="1" colspan="1" style="background-color:#CCFFCC;text-align:center;vertical-align:middle;">>100</td><td headers="hd_h_ml114.tu2_1_1_1_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>15-fold</td><td headers="hd_h_ml114.tu2_1_1_1_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NT</td></tr><tr><td headers="hd_h_ml114.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>Analog 3 (4)</b></td><td headers="hd_h_ml114.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5860517</td><td headers="hd_h_ml114.tu2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85098570" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85098570</a></td><td headers="hd_h_ml114.tu2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS002473503</td><td headers="hd_h_ml114.tu2_1_1_1_5" rowspan="1" colspan="1" style="background-color:#CCFFFF;text-align:center;vertical-align:middle;">RBBP9</td><td headers="hd_h_ml114.tu2_1_1_1_6" rowspan="1" colspan="1" style="background-color:#CCFFFF;text-align:center;vertical-align:middle;">5.0</td><td headers="hd_h_ml114.tu2_1_1_1_7" rowspan="1" colspan="1" style="background-color:#CCFFCC;text-align:center;vertical-align:middle;">>30 SHs</td><td headers="hd_h_ml114.tu2_1_1_1_8" rowspan="1" colspan="1" style="background-color:#CCFFCC;text-align:center;vertical-align:middle;">>20</td><td headers="hd_h_ml114.tu2_1_1_1_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>4-fold</td><td headers="hd_h_ml114.tu2_1_1_1_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NT</td></tr><tr><td headers="hd_h_ml114.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>Analog 4 (5)</b></td><td headers="hd_h_ml114.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5524574</td><td headers="hd_h_ml114.tu2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85098571" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85098571</a></td><td headers="hd_h_ml114.tu2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS002473504</td><td headers="hd_h_ml114.tu2_1_1_1_5" rowspan="1" colspan="1" style="background-color:#CCFFFF;text-align:center;vertical-align:middle;">RBBP9</td><td headers="hd_h_ml114.tu2_1_1_1_6" rowspan="1" colspan="1" style="background-color:#CCFFFF;text-align:center;vertical-align:middle;">9.1</td><td headers="hd_h_ml114.tu2_1_1_1_7" rowspan="1" colspan="1" style="background-color:#CCFFCC;text-align:center;vertical-align:middle;">>30 SHs</td><td headers="hd_h_ml114.tu2_1_1_1_8" rowspan="1" colspan="1" style="background-color:#CCFFCC;text-align:center;vertical-align:middle;">20 75-kDa SH, >20 all other SHs</td><td headers="hd_h_ml114.tu2_1_1_1_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2-fold</td><td headers="hd_h_ml114.tu2_1_1_1_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>100000</td></tr><tr><td headers="hd_h_ml114.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>Analog 5 (6)</b></td><td headers="hd_h_ml114.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">44141914</td><td headers="hd_h_ml114.tu2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85098573" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85098573</a></td><td headers="hd_h_ml114.tu2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS002473505</td><td headers="hd_h_ml114.tu2_1_1_1_5" rowspan="1" colspan="1" style="background-color:#CCFFFF;text-align:center;vertical-align:middle;">RBBP9</td><td headers="hd_h_ml114.tu2_1_1_1_6" rowspan="1" colspan="1" style="background-color:#CCFFFF;text-align:center;vertical-align:middle;">66% inhibition at 20 μM, IC<sub>50</sub> not determined</td><td headers="hd_h_ml114.tu2_1_1_1_7" rowspan="1" colspan="1" style="background-color:#CCFFCC;text-align:center;vertical-align:middle;">>30 SHs</td><td headers="hd_h_ml114.tu2_1_1_1_8" rowspan="1" colspan="1" style="background-color:#CCFFCC;text-align:center;vertical-align:middle;">>20</td><td headers="hd_h_ml114.tu2_1_1_1_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml114.tu2_1_1_1_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NT</td></tr><tr><td headers="hd_h_ml114.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>Prior Art</b></td><td headers="hd_h_ml114.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6603320</td><td headers="hd_h_ml114.tu2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/855836" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">855836</a></td><td headers="hd_h_ml114.tu2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS000028478</td><td headers="hd_h_ml114.tu2_1_1_1_5" rowspan="1" colspan="1" style="background-color:#CCFFFF;text-align:center;vertical-align:middle;">RBBP9</td><td headers="hd_h_ml114.tu2_1_1_1_6" rowspan="1" colspan="1" style="background-color:#CCFFFF;text-align:center;vertical-align:middle;">7.8</td><td headers="hd_h_ml114.tu2_1_1_1_7" rowspan="1" colspan="1" style="background-color:#CCFFCC;text-align:center;vertical-align:middle;">>30 SHs</td><td headers="hd_h_ml114.tu2_1_1_1_8" rowspan="1" colspan="1" style="background-color:#CCFFCC;text-align:center;vertical-align:middle;">>1000</td><td headers="hd_h_ml114.tu2_1_1_1_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>100-fold</td><td headers="hd_h_ml114.tu2_1_1_1_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">~100</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>*</dt><dd><div id="ml114.tfn1"><p class="no_margin">NT = not tested</p></div></dd></dl></div></div></div></div><div id="ml114.s6"><h2 id="_ml114_s6_">2. Project Description</h2><div id="ml114.s7"><h3>a. Original goal for probe characteristics</h3><p>The goal of the campaign was to discover compounds with inhibitory activity against RBBP9 that are selective among the serine hydrolases in mouse tissue as assessed by gel-based competitive-ABPP. Compounds of interest should exhibit an IC<sub>50</sub> of <10 μM, and preferably <1 μM.</p></div><div id="ml114.s8"><h3>b. Information for each Assay Implemented and Screening Run</h3><div id="ml114.s9"><h4>i. PubChem Bioassay Name(s), AID(s), Assay-Type (Primary, DR, Counterscreen, Secondary)</h4><div id="ml114.tu3" class="table"><h3><span class="title">PubChem BioAssay Table</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK50690/table/ml114.tu3/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml114.tu3_lrgtbl__"><table class="no_margin"><thead><tr><th id="hd_h_ml114.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">AID</th><th id="hd_h_ml114.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Assay Name</th><th id="hd_h_ml114.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Assay Type</th><th id="hd_h_ml114.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Target</th><th id="hd_h_ml114.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Powder Sample</th><th id="hd_h_ml114.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Compound Concentration</th></tr></thead><tbody><tr><td headers="hd_h_ml114.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1515" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1515</a></td><td headers="hd_h_ml114.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Primary biochemical high-throughput screening assay to measure RBBP9 inhibition</td><td headers="hd_h_ml114.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Primary Assay (1X, %INH)</td><td headers="hd_h_ml114.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">RBBP9</td><td headers="hd_h_ml114.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">No</td><td headers="hd_h_ml114.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">8 μM</td></tr><tr><td headers="hd_h_ml114.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1537" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1537</a></td><td headers="hd_h_ml114.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Confirmation biochemical high-throughput screening assay to measure RBBP9 inhibition</td><td headers="hd_h_ml114.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Confirmation Assay (3X, %INH)</td><td headers="hd_h_ml114.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">RBBP9</td><td headers="hd_h_ml114.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">No</td><td headers="hd_h_ml114.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">8 μM</td></tr><tr><td headers="hd_h_ml114.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1947" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1947</a></td><td headers="hd_h_ml114.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Fluorescence polarization-based counterscreen for RBBP9 inhibitors: primary biochemical high throughput screening assay to identify inhibitors of the serine hydrolase family member Fam108B</td><td headers="hd_h_ml114.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Counterscreen Assay</td><td headers="hd_h_ml114.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Fam108b</td><td headers="hd_h_ml114.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">No</td><td headers="hd_h_ml114.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">9.51 μM</td></tr><tr><td headers="hd_h_ml114.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1974" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1974</a></td><td headers="hd_h_ml114.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Fluorescence polarization-based counterscreen for RBBP9 inhibitors: primary biochemical high throughput screening assay to identify inhibitors of the oxidoreductase glutathione S- transferase omega 1(GSTO1)</td><td headers="hd_h_ml114.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Counterscreen Assay</td><td headers="hd_h_ml114.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">GSTO1</td><td headers="hd_h_ml114.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">No</td><td headers="hd_h_ml114.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5.96 μM</td></tr><tr><td headers="hd_h_ml114.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1978" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1978</a></td><td headers="hd_h_ml114.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Fluorescence polarization-based confirmation biochemical high throughput screening assay for inhibitors of the serine hydrolase family member Fam108b</td><td headers="hd_h_ml114.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Counterscreen Assay</td><td headers="hd_h_ml114.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Fam108b</td><td headers="hd_h_ml114.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">No</td><td headers="hd_h_ml114.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">9.51 μM</td></tr><tr><td headers="hd_h_ml114.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2176" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2176</a></td><td headers="hd_h_ml114.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Fluorescence polarization-based biochemical high throughput confirmation assay for inhibitors of the oxidoreductase glutathione S-transferase omega 1(GSTO1)</td><td headers="hd_h_ml114.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Counterscreen Assay</td><td headers="hd_h_ml114.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">GSTO1</td><td headers="hd_h_ml114.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">No</td><td headers="hd_h_ml114.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5.96 μM</td></tr><tr><td headers="hd_h_ml114.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2269" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2269</a></td><td headers="hd_h_ml114.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Late stage results from the probe development effort to identify inhibitors of Retinoblastoma Binding Protein 9 (RBBP9): Gel- based Activity-Based Protein Profiling (ABPP) Inhibition</td><td headers="hd_h_ml114.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Secondary Assay</td><td headers="hd_h_ml114.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">RBBP9</td><td headers="hd_h_ml114.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Yes</td><td headers="hd_h_ml114.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20 μM</td></tr><tr><td headers="hd_h_ml114.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2254" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2254</a></td><td headers="hd_h_ml114.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Late stage results from the probe development effort to identify inhibitors of Retinoblastoma Binding Protein 9 (RBBP9): Gel- based Activity-Based Protein Profiling (ABPP) IC<sub>50</sub></td><td headers="hd_h_ml114.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Secondary Assay</td><td headers="hd_h_ml114.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">RBBP9, anti- target serine hydrolases</td><td headers="hd_h_ml114.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Yes</td><td headers="hd_h_ml114.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.1 – 100 μM</td></tr><tr><td headers="hd_h_ml114.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2243" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2243</a></td><td headers="hd_h_ml114.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Late stage results from the probe development effort to identify inhibitors of Retinoblastoma Binding Protein 9 (RBBP9): Luminescence-based counterscreen assay to identify cytotoxic compounds</td><td headers="hd_h_ml114.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Secondary Assay</td><td headers="hd_h_ml114.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">HEK 293T cells</td><td headers="hd_h_ml114.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Yes</td><td headers="hd_h_ml114.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1 – 10 μM</td></tr><tr><td headers="hd_h_ml114.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2248" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2248</a></td><td headers="hd_h_ml114.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Late stage results from the probe development effort to identify inhibitors of Retinoblastoma Binding Protein 9 (RBBP9): Gel- based Activity-Based Protein Profiling (ABPP) Gel Filtration Assay</td><td headers="hd_h_ml114.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Secondary Assay</td><td headers="hd_h_ml114.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">RBBP9</td><td headers="hd_h_ml114.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Yes</td><td headers="hd_h_ml114.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">100 mM</td></tr><tr><td headers="hd_h_ml114.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1790" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1790</a></td><td headers="hd_h_ml114.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Summary of probe development efforts to identify inhibitors of Retinoblastoma binding protein 9 (RBBP9) (emetine)</td><td headers="hd_h_ml114.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">N/A</td><td headers="hd_h_ml114.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">N/A</td><td headers="hd_h_ml114.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">N/A</td><td headers="hd_h_ml114.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">N/A</td></tr><tr><td headers="hd_h_ml114.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2299" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2299</a></td><td headers="hd_h_ml114.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Summary of probe development efforts to identify inhibitors of Retinoblastoma binding protein 9 (RBBP9) (ester oxime))</td><td headers="hd_h_ml114.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">N/A</td><td headers="hd_h_ml114.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">N/A</td><td headers="hd_h_ml114.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">N/A</td><td headers="hd_h_ml114.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">N/A</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div id="ml114.tfn2"><p class="no_margin">N/A: Not applicable.</p></div></dd></dl></div></div></div></div><div id="ml114.s10"><h4>ii. Assay Rationale & Description</h4><div id="ml114.tu4" class="table"><h3><span class="title">Table of Assay Rationale and Description</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK50690/table/ml114.tu4/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml114.tu4_lrgtbl__"><table class="no_margin"><thead><tr><th id="hd_h_ml114.tu4_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">AID</th><th id="hd_h_ml114.tu4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Assay Rationale</th><th id="hd_h_ml114.tu4_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Assay Description</th><th id="hd_h_ml114.tu4_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Z′</th><th id="hd_h_ml114.tu4_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S:B</th></tr></thead><tbody><tr><td headers="hd_h_ml114.tu4_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1515" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1515</a></td><td headers="hd_h_ml114.tu4_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To measure the ability of compounds to inhibit RBBP9 activity</td><td headers="hd_h_ml114.tu4_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">In this assay, a fluorophosphonate-rhodamine (FP-Rh) probe which broadly targets enzymes from the serine hydrolase family is used to label RBBP9 in the presence of test compounds. The reaction is excited with linear polarized light and the intensity of the emitted light is measured as the polarization value (mP). As designed, test compounds that act as RBBP9 inhibitors will prevent RBBP9-probe interactions, thereby increasing the proportion of free (unbound) fluorescent probe in the well, leading to low fluorescence polarization in the well. Compounds were tested in singlicate at a final nominal concentration of 7.94 micromolar.</td><td headers="hd_h_ml114.tu4_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.75 +/− 0.03</td><td headers="hd_h_ml114.tu4_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1.54 +/− 0.03</td></tr><tr><td headers="hd_h_ml114.tu4_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1537" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1537</a></td><td headers="hd_h_ml114.tu4_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Confirmation of hit activity of compounds identified in the Primary Screen</td><td headers="hd_h_ml114.tu4_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Same as above except compounds were tested in triplicate.</td><td headers="hd_h_ml114.tu4_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.78 +/− 0.02</td><td headers="hd_h_ml114.tu4_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3.14 +/− 0.03</td></tr><tr><td headers="hd_h_ml114.tu4_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1947" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1947</a></td><td headers="hd_h_ml114.tu4_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Counterscreen to identify compounds that act as inhibitors Fam108B</td><td headers="hd_h_ml114.tu4_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">In this biochemical assay, recombinant Fam108B protein is incubated with test compounds and FP-Rh probe. The reaction is excited with linear polarized light and the intensity of the emitted light is measured as the polarization value (mP). As designed, test compounds that act as Fam 108B inhibitors will prevent Fam 108B-probe interactions, thereby increasing the proportion of free (unbound) fluorescent probe in the well, leading to low fluorescence polarization. Compounds were tested in singlicate at a final nominal concentration of 9.51 micromolar.</td><td headers="hd_h_ml114.tu4_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.83 +/− 0.03</td><td headers="hd_h_ml114.tu4_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1.46 +/− 0.07</td></tr><tr><td headers="hd_h_ml114.tu4_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1974" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1974</a></td><td headers="hd_h_ml114.tu4_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Counterscreen to identify compounds that act as inhibitors of GSTO1</td><td headers="hd_h_ml114.tu4_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">In this assay, recombinant GSTO1 protein is incubated with test compounds and a Rh-conjugated sulfonate ester (SE) activity-based probe. The reaction is excited with linear polarized light and the intensity of the emitted light is measured as the polarization value (mP). As designed, test compounds that act as GSTO1 inhibitors will prevent GSTO1-probe interactions, thereby increasing the proportion of free (unbound) fluorescent probe in the well, leading to low fluorescence polarization. Compounds are tested in singlicate at a final nominal concentration of 5.96 micromolar.</td><td headers="hd_h_ml114.tu4_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.80 +/− 0.05</td><td headers="hd_h_ml114.tu4_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2.08 +/− 0.21</td></tr><tr><td headers="hd_h_ml114.tu4_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1978" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1978</a></td><td headers="hd_h_ml114.tu4_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Confirmation of counterscreen to identify inhibitors of Fam108b</td><td headers="hd_h_ml114.tu4_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">In this biochemical assay, recombinant Fam108b protein is incubated with test compounds and FP-Rh probe. The reaction is excited with linear polarized light and the intensity of the emitted light is measured as the polarization value (mP). As designed, test compounds that act as Fam 108b inhibitors will prevent Fam 108b-probe interactions, thereby increasing the proportion of free (unbound) fluorescent probe in the well, leading to low fluorescence polarization. Compounds were tested in triplicate at a final nominal concentration of 9.51 micromolar.</td><td headers="hd_h_ml114.tu4_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.70 +/− 0.04</td><td headers="hd_h_ml114.tu4_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1.54 +/− 0.01</td></tr><tr><td headers="hd_h_ml114.tu4_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2176" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2176</a></td><td headers="hd_h_ml114.tu4_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Confirmation of counterscreen to identify inhibitors of GSTO1</td><td headers="hd_h_ml114.tu4_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">In this assay, recombinant GSTO1 protein is incubated with test compounds and a Rh-conjugated sulfonate ester (SE) activity-based probe. The reaction is excited with linear polarized light and the intensity of the emitted light is measured as the polarization value (mP). As designed, test compounds that act as GSTO1 inhibitors will prevent GSTO1-probe interactions, thereby increasing the proportion of free (unbound) fluorescent probe in the well, leading to low fluorescence polarization. Compounds are tested in triplicate at a final nominal concentration of 5.96 micromolar.</td><td headers="hd_h_ml114.tu4_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.84 +/− 0.04</td><td headers="hd_h_ml114.tu4_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3.19 +/− 0.14</td></tr><tr><td headers="hd_h_ml114.tu4_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2269" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2269</a></td><td headers="hd_h_ml114.tu4_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Confirmation of hit activity of compounds identified in the Primary Screen and the Confirmation Screen</td><td headers="hd_h_ml114.tu4_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">In this assay, a fluorophosphonate-rhodamine (FP-Rh) probe which broadly targets enzymes from the serine hydrolase family is used to label RBBP9 in the presence of test compounds. The reaction products are separated by SDS-PAGE and visualized in-gel using a flatbed fluorescence scanner. The percentage activity remaining is determined by measuring the integrated optical density of the bands. As designed, test compounds that act as RBBP9 inhibitors will prevent RBBP9-probe interactions, thereby increasing the proportion of free (unbound) fluorescent probe, leading to low fluorescence polarization in the band in the gel. Percent inhibition of recombinant RBBP9 (compound at 20 μM) was determined.</td><td headers="hd_h_ml114.tu4_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">N/A</td><td headers="hd_h_ml114.tu4_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">N/A</td></tr><tr><td headers="hd_h_ml114.tu4_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2254" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2254</a></td><td headers="hd_h_ml114.tu4_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To determine selectivity of compounds in proteomes</td><td headers="hd_h_ml114.tu4_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Same as above except IC<sub>50</sub> values are determined from dose-response curves from three trials at each inhibitor concentration (0.1–100 mM).</td><td headers="hd_h_ml114.tu4_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">N/A</td><td headers="hd_h_ml114.tu4_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">N/A</td></tr><tr><td headers="hd_h_ml114.tu4_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2243" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2243</a></td><td headers="hd_h_ml114.tu4_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To determine cytotoxicity of inhibitor compounds belonging to the oxime ester scaffold</td><td headers="hd_h_ml114.tu4_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">In this assay, HEK cells are incubated with test compounds, followed by determination of cell viability. The assay utilizes the CellTiter- Glo luminescent reagent to measure intracellular ATP in viable cells. Luciferase present in the reagent catalyzes the oxidation of beetle luciferin to oxyluciferin and light in the presence of cellular ATP. Well luminescence is directly proportional to ATP levels and cell viability. As designed, compounds that reduce cell viability will reduce ATP levels, luciferin oxidation and light production, resulting in decreased well luminescence. Compounds were tested in triplicate in a 10-point 1:3 dilution series starting at a nominal test concentration of 40 micromolar.</td><td headers="hd_h_ml114.tu4_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">N/A</td><td headers="hd_h_ml114.tu4_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">N/A</td></tr><tr><td headers="hd_h_ml114.tu4_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2248" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2248</a></td><td headers="hd_h_ml114.tu4_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To assess reversibility of binding of inhibitor compounds belonging to the oxime ester scaffold</td><td headers="hd_h_ml114.tu4_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">In this assay, a fraction of the enzyme-inhibitor mixture is passaged over a Sephadex G-25M column (GE Healthcare) before reaction with a fluorophosphonate-rhodamine (FP-Rh) probe which broadly targets enzymes from the serine hydrolase family is used to label RBBP9 in the presence of test compounds. The reaction products are separated by SDS-PAGE and visualized in-gel using a flatbed fluorescence scanner. The percentage activity remaining is determined by measuring the integrated optical density of the bands. As designed, test compounds that act as irreversible RBBP9 inhibitors will prevent RBBP9-probe interactions after gel filtration, thereby increasing the proportion of free (unbound) fluorescent probe, leading to low fluorescence polarization in the band in the gel. The compound’s reversibility of inhibition of RBBP9 was assessed.</td><td headers="hd_h_ml114.tu4_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">N/A</td><td headers="hd_h_ml114.tu4_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">N/A</td></tr><tr><td headers="hd_h_ml114.tu4_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1790" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1790</a></td><td headers="hd_h_ml114.tu4_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To summarize probe development efforts for inhibitors of RBBP9 (emetime)</td><td headers="hd_h_ml114.tu4_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">N/A</td><td headers="hd_h_ml114.tu4_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">N/A</td><td headers="hd_h_ml114.tu4_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">N/A</td></tr><tr><td headers="hd_h_ml114.tu4_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2299" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2299</a></td><td headers="hd_h_ml114.tu4_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To summarize probe development efforts for inhibitors of RBBP9 (ester oxime)</td><td headers="hd_h_ml114.tu4_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">N/A</td><td headers="hd_h_ml114.tu4_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">N/A</td><td headers="hd_h_ml114.tu4_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">N/A</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div id="ml114.tfn3"><p class="no_margin">N/A: Not applicable.</p></div></dd></dl></div></div></div><div id="ml114.tu5" class="table"><h3><span class="title">Table of Reagents and Source</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK50690/table/ml114.tu5/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml114.tu5_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml114.tu5_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">AID</th><th id="hd_h_ml114.tu5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">Reagent (Source)</th></tr></thead><tbody><tr><td headers="hd_h_ml114.tu5_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">RBBP9 Inhibition Assays (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1515" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1515</a> and <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1537" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1537</a>)</td><td headers="hd_h_ml114.tu5_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Recombinant RBBP9 (supplied by Assay Provider)<br />FP-Rh probe (supplied by Assay Provider)<br />Tris HCl (Sigma, part T3038)<br />NaCl (Sigma, part S6546)<br />Pluronic acid (Invitrogen, part P6866)<br />1536-well plates (Greiner, part 789176)</td></tr><tr><td headers="hd_h_ml114.tu5_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">RBBP9 Follow-up Assays (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2269" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2269</a> and <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2254" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2254</a>)</td><td headers="hd_h_ml114.tu5_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Recombinant RBBP9 protein (supplied by Assay Provider)<br />FP-rhodamine (supplied by Assay Provider)<br />Sodium Chloride (Fisher, part 980597)<br />1M Tris, pH 8.0 (Invitrogen, part T-3038)</td></tr><tr><td headers="hd_h_ml114.tu5_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Cytotoxicity Assay (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2243" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2243</a>)</td><td headers="hd_h_ml114.tu5_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">HEK cells (provided by Assay Provider)<br />Cell Titer-Glo (Promega, part <a href="/nuccore/22474626" class="bk_tag" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=nuccore">G75729</a>)<br />96-well plates (Corning, 3704)</td></tr><tr><td headers="hd_h_ml114.tu5_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">RBBP9 Gel Filtration Assay (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2248" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2248</a>)</td><td headers="hd_h_ml114.tu5_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Recombinant RBBP9 protein (provided by Assay Provider)<br />FP-rhodamine (provided by Assay Provider)<br />Sodium Chloride (Fisher, part 980597)<br />1M Tris, pH 8.0 (Invitrogen, part T-3038)<br />Sephadex G-25 (GE Healthcare, part 17-0851-01)</td></tr></tbody></table></div></div></div><div id="ml114.s11"><h4>iii. Summary of Results</h4><p>Following Primary screening in singlicate (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1515" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1515</a>), Confirmation of hit activity in triplicate
|
||
(<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1537" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1537</a>), and counterscreening by gel-based competitive-ABPP in proteomes to determine selectivity
|
||
(<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2269" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2269</a> and <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2254" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2254</a>), we identified an oxime ester class of inhibitor for probe development. Compound
|
||
<a href="/pcsubstance/?term=ML114[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML114</a> (CID 5934766, compound <b>1</b>
|
||
<a class="figpopup" href="/books/NBK50690/table/ml114.t2/?report=objectonly" target="object" rid-figpopup="figml114t2" rid-ob="figobml114t2">Table A2.1</a>
|
||
<a href="#ml114.s32">Appendix 2</a>) discovered from these efforts represents the first selective irreversible RBBP9
|
||
inhibitor (<a href="#ml114.s32">Appendix 2</a>, <a class="figpopup" href="/books/NBK50690/figure/ml114.f1/?report=objectonly" target="object" rid-figpopup="figml114f1" rid-ob="figobml114f1">Fig A2.1b</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2248" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2248</a>). Unlike the
|
||
reversible RBBP9 inhibitor emetine, this compound is not cytotoxic (<a href="#ml114.s32">Appendix 2</a>, <a class="figpopup" href="/books/NBK50690/figure/ml114.f2/?report=objectonly" target="object" rid-figpopup="figml114f2" rid-ob="figobml114f2">Fig A2.2</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2243" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2243</a>) and we anticipate it will be useful to determine the function of this uncharacterized enzyme.</p></div></div><div id="ml114.s12"><h3>c. Probe Optimization</h3><div id="ml114.s13"><h4>i. Description of SAR & chemistry strategy (including structure and data) that led to the probe</h4><div id="ml114.s14"><h5>Potency</h5><p>We identified three related compounds with oxime ester cores: two compounds had a left-hand oxime
|
||
substituent containing a thiazole (CIDs 1481894 and 44141914, compounds <b>2</b> and
|
||
<b>5,</b>
|
||
<a href="#ml114.s32">Appendix 2</a>, <a class="figpopup" href="/books/NBK50690/table/ml114.t2/?report=objectonly" target="object" rid-figpopup="figml114t2" rid-ob="figobml114t2">Table A2.1</a>), and the third
|
||
compound (CID 885318, compound <b>18</b>
|
||
<a href="#ml114.s33">Appendix 3</a>, <a class="figpopup" href="/books/NBK50690/table/ml114.t3/?report=objectonly" target="object" rid-figpopup="figml114t3" rid-ob="figobml114t3">Table A3.1</a>) had a left-hand cyclohexyldienone-containing substituent. An
|
||
initial round of SAR by purchase on the oxime ester core revealed that large structural
|
||
modifications, especially to the oxime leaving group, ablated inhibitory activity (<a href="#ml114.s33">Appendix 3</a>, <a class="figpopup" href="/books/NBK50690/table/ml114.t4/?report=objectonly" target="object" rid-figpopup="figml114t4" rid-ob="figobml114t4">Table A3.2</a>). Both the thiazole and cyclohexyldienone
|
||
structures are conjugated systems capable of stabilizing negative charge, which likely makes these
|
||
moieties good leaving groups during covalent modification [the right-hand substituent was
|
||
shown to remain bound to a serine nucleophile of RBBP9 (<a href="#ml114.s32">Appendix 2</a>, <a class="figpopup" href="/books/NBK50690/figure/ml114.f1/?report=objectonly" target="object" rid-figpopup="figml114f1" rid-ob="figobml114f1">Figure A2.1c</a>)]. The second round of SAR by purchase and synthesis
|
||
preserved the oxime ester core and the left-hand thiazole containing substituent common to compounds
|
||
<b>2</b> and <b>3</b> or the cyclohexyldienone containing substituent of compound <b>18</b> (<a href="#ml114.s33">Appendix 3</a>, <a class="figpopup" href="/books/NBK50690/table/ml114.t1/?report=objectonly" target="object" rid-figpopup="figml114t1" rid-ob="figobml114t1">Tables A3.1</a> and <a class="figpopup" href="/books/NBK50690/table/ml114.t2/?report=objectonly" target="object" rid-figpopup="figml114t2" rid-ob="figobml114t2">2</a>). For the thiazole, some steric bulk and structural rigidity was required on the right-hand side for RBBP9 inhibition, as small substituents (compounds <b>13</b>, <b>14</b>) were inactive; however, large groups (compounds <b>11</b>, <b>16</b>, <b>17</b>) were also not tolerated. A variety of electronically neutral (compounds <b>1</b>, <b>4</b>), weak electron-withdrawing (compounds <b>2</b>, <b>3</b>, <b>7–10</b>) or electron-donating (compound <b>5</b>) substituents were allowed; however, molecules with strong electron-withdrawing groups (compounds <b>6</b>, <b>12</b>) were inactive, possibly because they predisposed the compound to hydrolysis rather than RBBP9 reactivity. For the cyclohexyldienone, the initial hit (compound <b>18</b>) and its analogs (compounds <b>19</b>–<b>22</b>) were less selective and were not extensively pursued. Overall, the probe (compound <b>1</b>) with the left-hand thiazole and right hand cyclohexyl was the most potent and selective compound tested, and was ~3-fold more potent than the top initial hit (compound <b>2</b>).</p></div><div id="ml114.s15"><h5>Selectivity</h5><p>As a class, the oxime esters were highly selective as assessed by their anti-target reactivity by
|
||
competitive-ABPP. At 20µM, only compounds <b>5</b>, <b>29</b>, and <b>30</b>
|
||
showed evidence of anti-target reactivity (<a class="figpopup" href="/books/NBK50690/table/ml114.t2/?report=objectonly" target="object" rid-figpopup="figml114t2" rid-ob="figobml114t2">Table A2.1</a>
|
||
<a href="#ml114.s32">Appendix 2</a>, <a class="figpopup" href="/books/NBK50690/table/ml114.t3/?report=objectonly" target="object" rid-figpopup="figml114t3" rid-ob="figobml114t3">Tables 2</a> & <a class="figpopup" href="/books/NBK50690/table/ml114.t4/?report=objectonly" target="object" rid-figpopup="figml114t4" rid-ob="figobml114t4">A3.3</a>
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||
<a href="#ml114.s33">Appendix 3</a>, <a class="figpopup" href="/books/NBK50690/figure/ml114.f1/?report=objectonly" target="object" rid-figpopup="figml114f1" rid-ob="figobml114f1">Figure A2.1d</a>
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||
<a href="#ml114.s32">Appendix 2</a>). Additionally, the highly structurally-related oxime ester compounds screened by uHTS (CIDs 1481894, 5135022, 3427192, 1481895, 885318, 710899, 2841783) all showed very low activity (<2.3%) in other bioassays (each tested in >300 bioassays), indicating that, as a class, this type of oxime ester scaffold is not generally active.</p></div></div></div></div><div id="ml114.s16"><h2 id="_ml114_s16_">3. Probe</h2><div id="ml114.s17"><h3>a. Chemical name of probe compound</h3><p>[1-(1,3-thiazol-2-yl)ethylideneamino] cyclohexanecarboxylate [<a href="/pcsubstance/?term=ML114[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML114</a>]</p></div><div id="ml114.s18"><h3>b. Probe chemical structure</h3><div id="ml114.fu2" class="figure"><div class="graphic"><img src="/books/NBK50690/bin/ml114fu2.jpg" alt="Image ml114fu2" /></div></div></div><div id="ml114.s19"><h3>c. Structural Verification Information of probe SID</h3><ol class="lower-roman"><li class="half_rhythm"><div>1H NMR (400 MHz, CDCl<sub>3</sub>) δ 7.91 (d, J = 3.2Hz, 1H), 7.44 (d, J = 3.2Hz, 1H), 2.57–2.51 (m, 1H), 2.54 (s, 3H), 2.10–1.96 (m, 2H), 1.9–1.77 (m, 2H), 1.75–1.65 (m, 1H), 1.65–1.51 (m, 2H), 1.44–1.24 (m, 3H), purity >95%.</div></li><li class="half_rhythm"><div>high-res MS analysis (ESI-TOF): M+H<sup>+</sup> expected: 253.1005, M+H<sup>+</sup> observed: 253.1014</div></li></ol></div><div id="ml114.s20"><h3>d. PubChem CID</h3><p>CID 5934766</p></div><div id="ml114.s21"><h3>e. Vendor</h3><p>Key Organics, catalog number 9w-0837</p></div><div id="ml114.s22"><h3>f. MLS#'s of probe molecule and five related samples that were submitted to the SMR collection</h3><p>MLS002473500 (see table in <a href="#ml114.s5">section 1</a>).</p></div><div id="ml114.s23"><h3>g. Mode of action for biological activity of probe</h3><p>We have shown that CID 5934766 (referred to as compound <b>1</b> in the <a href="#ml114.s30">Appendix</a>) forms a
|
||
covalent adduct with RBBP9 by demonstrating that blockade of FP-rhodamine labeling is not reversed
|
||
by gel filtration and by identifying the acylated RBBP9 active site nucleophile (S75) by mass
|
||
spectrometry (see <a href="#ml114.s32">Appendix 2</a>, <a class="figpopup" href="/books/NBK50690/figure/ml114.f1/?report=objectonly" target="object" rid-figpopup="figml114f1" rid-ob="figobml114f1">Figures A2.1b and A2.1c</a>). Even though <b>1</b> contains a reactive chemical moiety, this compound selectively inhibits RBBP9 in the mouse brain membrane proteome. As the biological function of RBBP9 is unknown, the biological effects of RBBP9 inhibition are currently unknown. We therefore anticipate that this oxime ester inhibitor, and future compounds derived from this chemically tractable scaffold, will assist the assignment of an enzymatic function of RBBP9 in biological systems.</p></div><div id="ml114.s24"><h3>h. Detailed synthetic pathway</h3><div id="ml114.fu3" class="figure"><div class="graphic"><img src="/books/NBK50690/bin/ml114fu3.jpg" alt="Image ml114fu3" /></div></div><div id="ml114.s25"><h4>1-(thiazol-2-yl)ethanone oxime (B)</h4><p>Sodium acetate (2.84 g, 34.6 mmol) was added to a solution of hydroxylamine hydrochloride (2.4g, 24.6 mmol) in EtOH (60 mL) at room temperature. After being stirred for 30 minutes, 2-acetylthiazole (<b>A</b>) (3.26 mL, 30.2 mmol) was added dropwise over 1 hour. After 2 additional hours of stirring, the reaction was quenched with water (added dropwise over 30 minutes). The mixture was extracted with EtOAc and the combined organic layer was washed with brine, dried over anhydrous MgSO<sub>4</sub>, and concentrated by rotary evaporation under reduced pressure. The crude product was purified by flash column chromatography on silica gel in hexane-EtOAc (4:1) to afford 1-(thiazol-2-yl)ethanone oxime (<b>B</b>) (20%).</p></div><div id="ml114.s26"><h4>Aryl/Acyl Oxime Ester (D)</h4><p>1-(thiazol-2-yl)ethanone oxime (<b>B</b>) (0.128 g, 1 mmol) was added to an aryl or acyl chloride (<b>C</b>) (1.5 mmol) in the presence of Et<sub>3</sub>N (0.32 mL, 2.3 mmol) at 0 °C. After stirring for 1 hour, the mixture was quenched with 1 N HCl, extracted with CH<sub>2</sub>Cl<sub>2</sub>, washed with brine, dried over MgSO<sub>4</sub>, and concentrated by rotary evaporation under reduced pressure. Purification by flash column chromatography affords the target oxime ester (<b>D</b>) in good yield (>60%).</p></div></div><div id="ml114.s27"><h3>i. Summary of probe properties (solubility, absorbance/fluorescence, reactivity, toxicity, etc.)</h3><p>ADMET BBB, −0.1400; ADMET BBB leve, l 2; ADMET absorption level, 0; ADMET solubility, −3.302; ADMET solubility level, 3</p><p>Solubility of the probe in PBS (137 mM NaCl, 2.7 mM KCl, 10 mM sodium phosphate dibasic, 2 mM
|
||
potassium phosphate monobasic, pH 7.4) at room temperature was determined to be 26.2 µM. The probe
|
||
has a half-life of 45 hours in PBS at room temperature (tested at 10 µM, <a class="figpopup" href="/books/NBK50690/figure/ml114.f3/?report=objectonly" target="object" rid-figpopup="figml114f3" rid-ob="figobml114f3">Figure A2.3</a>
|
||
<a href="#ml114.s32">Appendix 2</a>).</p><p>The probe compound showed no reactivity with glutathione (100 µM), indicating that it is not generally cysteine reactive, but rather has a tempered electrophilicity and specific structural elements that direct reactivity towards GSTO1. An irreversible probe has some distinct advantages over reversible analogs. Targets can be readily characterized by methods such as mass spectrometry and click chemistry-ABPP, required dosing is often lower, irreversible compounds are not as sensitive to pharmacokinetic parameters, and administration can induce long-lasting inhibition (<a class="bk_pop" href="#ml114.r10">10</a>). In the case of the EGFR inhibitor PD 0169414, its irreversibility and high selectivity were credited with producing prolonged inhibition of the target, alleviating concerns over short plasma half-lives and reducing the need for high peak plasma levels, thus minimizing potential nonspecific toxic effects (<a class="bk_pop" href="#ml114.r11">11</a>).</p><p>Indeed, over a third of enzymatic drug targets are irreversibly inhibited by currently marketed drugs (<a class="bk_pop" href="#ml114.r12">12</a>). Examples of covalent enzyme-inhibitor pairs include serine type D-Ala-D-Ala carboxypeptidase, which is covalently modified by all beta-lactam antibiotics, acetylcholinesterase, whose active site serine undergoes covalent modification by pyridostigmine, prostaglandin-endoperoxide synthase, which is the target of the ubiquitously prescribed aspirin, aromatase, which is irreversibly modified by exemestane, monoamine oxidase, which is covalently modified by L-deprenyl, thymidylate synthase, which is covalently modified by floxuridine, H+/K+ ATPase, which undergoes covalent modification by omaprazole, esmoprazole, and lanoprazole, and triacylglycerol lipase, whose serine nucleophile is targeted by orlistat (<a class="bk_pop" href="#ml114.r12">12</a>).</p></div><div id="ml114.s28"><h3>j. Probe properties</h3><div id="ml114.tu6" class="table"><h3><span class="title">Properties Computed from Structure</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK50690/table/ml114.tu6/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml114.tu6_lrgtbl__"><table class="no_margin"><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">PubChem CID</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">5934766</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">PubChem SID</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">85098567</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">IUPAC Name</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">[1-(1,3-thiazol-2-yl)ethylideneamino] cyclohexanecarboxylate</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MLS</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">None</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MF</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">C<sub>12</sub>H<sub>16</sub>N<sub>2</sub>O<sub>2</sub>S</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MW</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">252.33264</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Formal Charge</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H Acceptor</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">4</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H Donor</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Heavy Atom Count</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">17</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Rotatable Bonds</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">4</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Rings</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Stereoatoms</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">AlogP</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2.448</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">logD</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2.439</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">XLogP3-AA</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">3.4</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Polar surface area</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">79.79</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Aqueous solubility<sup><a class="bk_pop" href="#ml114.tfn4">a</a></sup></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">26.2µM</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Aqueous stability<sup><a class="bk_pop" href="#ml114.tfn4">a</a></sup></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">half-life of 45 hours</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Reactivity with Glutathione<sup><a class="bk_pop" href="#ml114.tfn4">a</a></sup></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">none</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Mechanism of Action</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Irreversible (covalent) inhibitor of RBBP9</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">ADMET BBB<sup><a class="bk_pop" href="#ml114.tfn5">b</a></sup></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">−0.1400</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">ADMET BBB level<sup><a class="bk_pop" href="#ml114.tfn6">c</a></sup></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">ADMET absorption level<sup><a class="bk_pop" href="#ml114.tfn7">d</a></sup></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">ADMET solubility<sup><a class="bk_pop" href="#ml114.tfn8">e</a></sup></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">−3.302</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">ADMET solubility level<sup>f</sup></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">3</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Vendor</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Key Organics</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Vendor Catalog Number</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">9w-0837</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>a</dt><dd><div id="ml114.tfn4"><p class="no_top_margin">determined according to NIH guidelines</p></div></dd><dt>b</dt><dd><div id="ml114.tfn5"><p class="no_top_margin">ADMET_BBB: Log of Brain/Blood partition coefficient (LogBB). See (<a class="bk_pop" href="#ml114.r13">13</a>) for details on this method.</p></div></dd><dt>c</dt><dd><div id="ml114.tfn6"><p class="no_top_margin">ADMET_BBB_Level: Ranking of the LogBB values into one of the following levels (see (<a class="bk_pop" href="#ml114.r13">13</a>, <a class="bk_pop" href="#ml114.r14">14</a>) for
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details):</p><p>0: Very High 1: High 2: Medium 3: Low</p><p>4: Undefined (molecule is outside the confidence area of the regression model).</p></div></dd><dt>d</dt><dd><div id="ml114.tfn7"><p class="no_top_margin">ADMET Passive Intestinal Absorption properties. A ranking of the molecule into one of the following levels (see (<a class="bk_pop" href="#ml114.r13">13</a>, <a class="bk_pop" href="#ml114.r14">14</a>) for details):</p><p>0: Good 1: Moderate 2: Poor 3: Very Poor</p></div></dd><dt>e</dt><dd><div id="ml114.tfn8"><p class="no_top_margin">ADMET_Solubility: Log of the water solubility at 25 degrees, LogSw, in mol/L. See (<a class="bk_pop" href="#ml114.r13">13</a>, <a class="bk_pop" href="#ml114.r14">14</a>) for more information.</p></div></dd></dl></div></div></div></div><div id="ml114.s29"><h3>k. Dose Response Curve for Probe</h3><p>Below is the IC50 Curve for Probe Compound as determined by gel-based competitive-ABPP with FP-Rh. Calculated IC50 = 0.63 µM.</p><div id="ml114.fu4" class="figure"><div class="graphic"><img src="/books/NBK50690/bin/ml114fu4.jpg" alt="Image ml114fu4" /></div></div></div></div><div id="ml114.s30"><h2 id="_ml114_s30_">4. Appendices</h2><div id="ml114.s31"><h3>Appendix 1. RBBP9 Inhibitors SAR Table</h3><div id="ml114.t1" class="table"><h3><span class="label">Table A1.1</span><span class="title">RBBP9 Inhibitors SAR Table (Oxime Ester Scaffold)</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK50690/table/ml114.t1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml114.t1_lrgtbl__"><table class="no_margin"><thead><tr><th id="hd_h_ml114.t1_1_1_1_1" rowspan="2" colspan="1" headers="hd_h_ml114.t1_1_1_1_1" style="text-align:center;vertical-align:middle;">Compound</th><th id="hd_h_ml114.t1_1_1_1_2" rowspan="2" colspan="1" headers="hd_h_ml114.t1_1_1_1_2" style="text-align:center;vertical-align:middle;">Scripps ID</th><th id="hd_h_ml114.t1_1_1_1_3" rowspan="2" colspan="1" headers="hd_h_ml114.t1_1_1_1_3" style="text-align:center;vertical-align:middle;">Structure</th><th id="hd_h_ml114.t1_1_1_1_4" rowspan="2" colspan="1" headers="hd_h_ml114.t1_1_1_1_4" style="text-align:center;vertical-align:middle;">CID</th><th id="hd_h_ml114.t1_1_1_1_5" rowspan="2" colspan="1" headers="hd_h_ml114.t1_1_1_1_5" style="text-align:center;vertical-align:middle;">SID</th><th id="hd_h_ml114.t1_1_1_1_6" rowspan="2" colspan="1" headers="hd_h_ml114.t1_1_1_1_6" style="text-align:center;vertical-align:middle;">MLS ID</th><th id="hd_h_ml114.t1_1_1_1_7" rowspan="2" colspan="1" headers="hd_h_ml114.t1_1_1_1_7" style="text-align:center;vertical-align:middle;">Vendor</th><th id="hd_h_ml114.t1_1_1_1_8" rowspan="2" colspan="1" headers="hd_h_ml114.t1_1_1_1_8" style="text-align:center;vertical-align:middle;">Vendor Catalog ID</th><th id="hd_h_ml114.t1_1_1_1_9" colspan="4" rowspan="1" style="text-align:center;vertical-align:middle;">Probe Development Assays</th></tr><tr><th headers="hd_h_ml114.t1_1_1_1_9" id="hd_h_ml114.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">RBBP9ABBP IC<sub>50</sub> [<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2254" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2254</a>] (nM)</th><th headers="hd_h_ml114.t1_1_1_1_9" id="hd_h_ml114.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Inhibition of purified RBBP9 (20 μM) [<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2269" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2269</a>] (%INH)</th><th headers="hd_h_ml114.t1_1_1_1_9" id="hd_h_ml114.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Gel Filtration Assay [<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2248" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2248</a>]</th><th headers="hd_h_ml114.t1_1_1_1_9" id="hd_h_ml114.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Cytotoxicity Assay (CC<sub>50</sub>) [<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2243" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2243</a>] (nM)</th></tr></thead><tbody><tr><td headers="hd_h_ml114.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>PROBE</b></td><td headers="hd_h_ml114.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SR-0100030 7014-2</td><td headers="hd_h_ml114.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50690/bin/ml114fu5.jpg" alt="Image ml114fu5.jpg" /></div></td><td headers="hd_h_ml114.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5934766</td><td headers="hd_h_ml114.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85098567" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85098567</a></td><td headers="hd_h_ml114.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS002 473500</td><td headers="hd_h_ml114.t1_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Key Organics</td><td headers="hd_h_ml114.t1_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">9w- 0837</td><td headers="hd_h_ml114.t1_1_1_1_9 hd_h_ml114.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">635</td><td headers="hd_h_ml114.t1_1_1_1_9 hd_h_ml114.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">91</td><td headers="hd_h_ml114.t1_1_1_1_9 hd_h_ml114.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Irreversible</td><td headers="hd_h_ml114.t1_1_1_1_9 hd_h_ml114.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>100000</td></tr><tr><td headers="hd_h_ml114.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Analog 1</td><td headers="hd_h_ml114.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SR-0100068 9006-1</td><td headers="hd_h_ml114.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50690/bin/ml114fu6.jpg" alt="Image ml114fu6.jpg" /></div></td><td headers="hd_h_ml114.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1481894</td><td headers="hd_h_ml114.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85098568" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85098568</a></td><td headers="hd_h_ml114.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS002 473501</td><td headers="hd_h_ml114.t1_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Key Organics</td><td headers="hd_h_ml114.t1_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6w- 0842</td><td headers="hd_h_ml114.t1_1_1_1_9 hd_h_ml114.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1900</td><td headers="hd_h_ml114.t1_1_1_1_9 hd_h_ml114.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">78</td><td headers="hd_h_ml114.t1_1_1_1_9 hd_h_ml114.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">See below<sup><a class="bk_pop" href="#ml114.tfn9">*</a></sup></td><td headers="hd_h_ml114.t1_1_1_1_9 hd_h_ml114.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">See below<sup><a class="bk_pop" href="#ml114.tfn10">†</a></sup></td></tr><tr><td headers="hd_h_ml114.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Analog 2</td><td headers="hd_h_ml114.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SR- 0100067 9216-2</td><td headers="hd_h_ml114.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50690/bin/ml114fu7.jpg" alt="Image ml114fu7.jpg" /></div></td><td headers="hd_h_ml114.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3427192</td><td headers="hd_h_ml114.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85098569" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85098569</a></td><td headers="hd_h_ml114.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS002 473502</td><td headers="hd_h_ml114.t1_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Key Organics</td><td headers="hd_h_ml114.t1_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">9w- 0835</td><td headers="hd_h_ml114.t1_1_1_1_9 hd_h_ml114.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5700</td><td headers="hd_h_ml114.t1_1_1_1_9 hd_h_ml114.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">76</td><td headers="hd_h_ml114.t1_1_1_1_9 hd_h_ml114.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">See below<sup><a class="bk_pop" href="#ml114.tfn9">*</a></sup></td><td headers="hd_h_ml114.t1_1_1_1_9 hd_h_ml114.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">See below<sup><a class="bk_pop" href="#ml114.tfn10">†</a></sup></td></tr><tr><td headers="hd_h_ml114.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Analog 3</td><td headers="hd_h_ml114.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SR- 0200000 0166-1</td><td headers="hd_h_ml114.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50690/bin/ml114fu8.jpg" alt="Image ml114fu8.jpg" /></div></td><td headers="hd_h_ml114.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5860517</td><td headers="hd_h_ml114.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85098570" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85098570</a></td><td headers="hd_h_ml114.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS002 473503</td><td headers="hd_h_ml114.t1_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml114.t1_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml114.t1_1_1_1_9 hd_h_ml114.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5000</td><td headers="hd_h_ml114.t1_1_1_1_9 hd_h_ml114.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">62</td><td headers="hd_h_ml114.t1_1_1_1_9 hd_h_ml114.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">See below<sup><a class="bk_pop" href="#ml114.tfn9">*</a></sup></td><td headers="hd_h_ml114.t1_1_1_1_9 hd_h_ml114.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">See below<sup><a class="bk_pop" href="#ml114.tfn10">†</a></sup></td></tr><tr><td headers="hd_h_ml114.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Analog 4</td><td headers="hd_h_ml114.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SR- 0100030 7018-3</td><td headers="hd_h_ml114.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50690/bin/ml114fu9.jpg" alt="Image ml114fu9.jpg" /></div></td><td headers="hd_h_ml114.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5524574</td><td headers="hd_h_ml114.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85098571" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85098571</a></td><td headers="hd_h_ml114.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS002 473504</td><td headers="hd_h_ml114.t1_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Key Organics</td><td headers="hd_h_ml114.t1_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6w- 0841</td><td headers="hd_h_ml114.t1_1_1_1_9 hd_h_ml114.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">9100</td><td headers="hd_h_ml114.t1_1_1_1_9 hd_h_ml114.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">60</td><td headers="hd_h_ml114.t1_1_1_1_9 hd_h_ml114.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">See below<sup><a class="bk_pop" href="#ml114.tfn9">*</a></sup></td><td headers="hd_h_ml114.t1_1_1_1_9 hd_h_ml114.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>100000</td></tr><tr><td headers="hd_h_ml114.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Analog 5</td><td headers="hd_h_ml114.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SR-0200000 0168-1</td><td headers="hd_h_ml114.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50690/bin/ml114fu10.jpg" alt="Image ml114fu10.jpg" /></div></td><td headers="hd_h_ml114.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">44141914</td><td headers="hd_h_ml114.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85098573" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85098573</a></td><td headers="hd_h_ml114.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS002 473505</td><td headers="hd_h_ml114.t1_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml114.t1_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml114.t1_1_1_1_9 hd_h_ml114.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">See below<sup><a class="bk_pop" href="#ml114.tfn11">‡</a></sup></td><td headers="hd_h_ml114.t1_1_1_1_9 hd_h_ml114.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">66</td><td headers="hd_h_ml114.t1_1_1_1_9 hd_h_ml114.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">See below<sup><a class="bk_pop" href="#ml114.tfn9">*</a></sup></td><td headers="hd_h_ml114.t1_1_1_1_9 hd_h_ml114.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">See below<sup><a class="bk_pop" href="#ml114.tfn10">†</a></sup></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>*</dt><dd><div id="ml114.tfn9"><p class="no_margin">Analogs 1 through 5 were not tested in the Gel Filtration Assay because this is a mechanistic assay and these related compounds will all interact covalently in the same way with RBBP9.</p></div></dd><dt>†</dt><dd><div id="ml114.tfn10"><p class="no_margin">Analogs 1, 2, 3, and 5 were not tested in the Cytotoxicity Assay.</p></div></dd><dt>‡</dt><dd><div id="ml114.tfn11"><p class="no_margin">Analog 5 was not tested because it was less selective than the lead compound.</p></div></dd></dl></div></div></div></div><div id="ml114.s32"><h3>Appendix 2. Assay Provider/Probe Development Assays</h3><div id="ml114.t2" class="table"><h3><span class="label">Table A2.1</span><span class="title">Comparative data on similar compound structures establishing SAR (right-hand derivatization)</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK50690/table/ml114.t2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml114.t2_lrgtbl__"><table class="no_margin"><thead><tr><th id="hd_h_ml114.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Number</th><th id="hd_h_ml114.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Structure</th><th id="hd_h_ml114.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Chemist or Vendor</th><th id="hd_h_ml114.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Catalog/Notebook Number</th><th id="hd_h_ml114.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">PubChem CID</th><th id="hd_h_ml114.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">PubChem SID</th><th id="hd_h_ml114.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS Number</th><th id="hd_h_ml114.t2_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IC<sub>50</sub> (nM) ABPP</th><th id="hd_h_ml114.t2_1_1_1_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">%Inhibition purified RBBP9 (20 μM)</th><th id="hd_h_ml114.t2_1_1_1_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Anti-targets<sup><a class="bk_pop" href="#ml114.tfn13">□</a></sup> (20 μM)</th></tr></thead><tbody><tr><td headers="hd_h_ml114.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml114.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50690/bin/ml114fu11.jpg" alt="Image ml114fu11.jpg" /></div></td><td headers="hd_h_ml114.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Key Organics</td><td headers="hd_h_ml114.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">9w-0837</td><td headers="hd_h_ml114.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5934766</td><td headers="hd_h_ml114.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85098567" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85098567</a></td><td headers="hd_h_ml114.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS002473500</td><td headers="hd_h_ml114.t2_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">635</td><td headers="hd_h_ml114.t2_1_1_1_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">91</td><td headers="hd_h_ml114.t2_1_1_1_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td></tr><tr><td headers="hd_h_ml114.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml114.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50690/bin/ml114fu12.jpg" alt="Image ml114fu12.jpg" /></div></td><td headers="hd_h_ml114.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Key Organics</td><td headers="hd_h_ml114.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6w-0842</td><td headers="hd_h_ml114.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1481894</td><td headers="hd_h_ml114.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85098568" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85098568</a></td><td headers="hd_h_ml114.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS002473501</td><td headers="hd_h_ml114.t2_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1900</td><td headers="hd_h_ml114.t2_1_1_1_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">78</td><td headers="hd_h_ml114.t2_1_1_1_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td></tr><tr><td headers="hd_h_ml114.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml114.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50690/bin/ml114fu13.jpg" alt="Image ml114fu13.jpg" /></div></td><td headers="hd_h_ml114.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Key Organics</td><td headers="hd_h_ml114.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">9w-0835</td><td headers="hd_h_ml114.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3427192</td><td headers="hd_h_ml114.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85098569" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85098569</a></td><td headers="hd_h_ml114.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS002473502</td><td headers="hd_h_ml114.t2_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5700</td><td headers="hd_h_ml114.t2_1_1_1_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">76</td><td headers="hd_h_ml114.t2_1_1_1_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td></tr><tr><td headers="hd_h_ml114.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml114.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50690/bin/ml114fu14.jpg" alt="Image ml114fu14.jpg" /></div></td><td headers="hd_h_ml114.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">DAB</td><td headers="hd_h_ml114.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">DAB-II- 296</td><td headers="hd_h_ml114.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5860517</td><td headers="hd_h_ml114.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85098570" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85098570</a></td><td headers="hd_h_ml114.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS002473503</td><td headers="hd_h_ml114.t2_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5000</td><td headers="hd_h_ml114.t2_1_1_1_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">62</td><td headers="hd_h_ml114.t2_1_1_1_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td></tr><tr><td headers="hd_h_ml114.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5</td><td headers="hd_h_ml114.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50690/bin/ml114fu15.jpg" alt="Image ml114fu15.jpg" /></div></td><td headers="hd_h_ml114.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Key Organics</td><td headers="hd_h_ml114.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6w-0841</td><td headers="hd_h_ml114.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5524574</td><td headers="hd_h_ml114.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85098571" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85098571</a></td><td headers="hd_h_ml114.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS002473504</td><td headers="hd_h_ml114.t2_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">9100</td><td headers="hd_h_ml114.t2_1_1_1_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">60</td><td headers="hd_h_ml114.t2_1_1_1_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">75-kDa SH</td></tr><tr><td headers="hd_h_ml114.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6</td><td headers="hd_h_ml114.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50690/bin/ml114fu16.jpg" alt="Image ml114fu16.jpg" /></div></td><td headers="hd_h_ml114.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">DAB/MW</td><td headers="hd_h_ml114.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MW-I-18</td><td headers="hd_h_ml114.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">44141913</td><td headers="hd_h_ml114.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85098572" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85098572</a></td><td headers="hd_h_ml114.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">-</td><td headers="hd_h_ml114.t2_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">See below<sup><a class="bk_pop" href="#ml114.tfn12">*</a></sup></td><td headers="hd_h_ml114.t2_1_1_1_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">15</td><td headers="hd_h_ml114.t2_1_1_1_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td></tr><tr><td headers="hd_h_ml114.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">7</td><td headers="hd_h_ml114.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50690/bin/ml114fu17.jpg" alt="Image ml114fu17.jpg" /></div></td><td headers="hd_h_ml114.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">DAB/MW</td><td headers="hd_h_ml114.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MW-I-11</td><td headers="hd_h_ml114.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">44141914</td><td headers="hd_h_ml114.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85098573" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85098573</a></td><td headers="hd_h_ml114.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS002473505</td><td headers="hd_h_ml114.t2_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">See below<sup><a class="bk_pop" href="#ml114.tfn12">*</a></sup></td><td headers="hd_h_ml114.t2_1_1_1_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">66</td><td headers="hd_h_ml114.t2_1_1_1_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td></tr><tr><td headers="hd_h_ml114.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">8</td><td headers="hd_h_ml114.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50690/bin/ml114fu18.jpg" alt="Image ml114fu18.jpg" /></div></td><td headers="hd_h_ml114.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Key Organics</td><td headers="hd_h_ml114.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">9w-0836</td><td headers="hd_h_ml114.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6280709</td><td headers="hd_h_ml114.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85098574" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85098574</a></td><td headers="hd_h_ml114.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">-</td><td headers="hd_h_ml114.t2_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">See below<sup><a class="bk_pop" href="#ml114.tfn12">*</a></sup></td><td headers="hd_h_ml114.t2_1_1_1_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">63</td><td headers="hd_h_ml114.t2_1_1_1_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td></tr><tr><td headers="hd_h_ml114.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">9</td><td headers="hd_h_ml114.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50690/bin/ml114fu19.jpg" alt="Image ml114fu19.jpg" /></div></td><td headers="hd_h_ml114.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Key Organics</td><td headers="hd_h_ml114.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6w-0843</td><td headers="hd_h_ml114.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1481895</td><td headers="hd_h_ml114.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85098575" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85098575</a></td><td headers="hd_h_ml114.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">-</td><td headers="hd_h_ml114.t2_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">See below<sup><a class="bk_pop" href="#ml114.tfn12">*</a></sup></td><td headers="hd_h_ml114.t2_1_1_1_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">64</td><td headers="hd_h_ml114.t2_1_1_1_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td></tr><tr><td headers="hd_h_ml114.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">10</td><td headers="hd_h_ml114.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50690/bin/ml114fu20.jpg" alt="Image ml114fu20.jpg" /></div></td><td headers="hd_h_ml114.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Key Organics</td><td headers="hd_h_ml114.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6w-0840</td><td headers="hd_h_ml114.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6346382</td><td headers="hd_h_ml114.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85098576" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85098576</a></td><td headers="hd_h_ml114.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">-</td><td headers="hd_h_ml114.t2_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">See below<sup><a class="bk_pop" href="#ml114.tfn12">*</a></sup></td><td headers="hd_h_ml114.t2_1_1_1_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">66</td><td headers="hd_h_ml114.t2_1_1_1_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td></tr><tr><td headers="hd_h_ml114.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">11</td><td headers="hd_h_ml114.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50690/bin/ml114fu21.jpg" alt="Image ml114fu21.jpg" /></div></td><td headers="hd_h_ml114.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">DAB</td><td headers="hd_h_ml114.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">DAB-II- 297</td><td headers="hd_h_ml114.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">44141915</td><td headers="hd_h_ml114.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85098577" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85098577</a></td><td headers="hd_h_ml114.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">-</td><td headers="hd_h_ml114.t2_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">See below<sup><a class="bk_pop" href="#ml114.tfn12">*</a></sup></td><td headers="hd_h_ml114.t2_1_1_1_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml114.t2_1_1_1_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td></tr><tr><td headers="hd_h_ml114.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">12</td><td headers="hd_h_ml114.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50690/bin/ml114fu22.jpg" alt="Image ml114fu22.jpg" /></div></td><td headers="hd_h_ml114.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Key Organics</td><td headers="hd_h_ml114.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">9w-0838</td><td headers="hd_h_ml114.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">9632052</td><td headers="hd_h_ml114.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85098578" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85098578</a></td><td headers="hd_h_ml114.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">-</td><td headers="hd_h_ml114.t2_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">See below<sup><a class="bk_pop" href="#ml114.tfn12">*</a></sup></td><td headers="hd_h_ml114.t2_1_1_1_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">46</td><td headers="hd_h_ml114.t2_1_1_1_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td></tr><tr><td headers="hd_h_ml114.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">13</td><td headers="hd_h_ml114.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50690/bin/ml114fu23.jpg" alt="Image ml114fu23.jpg" /></div></td><td headers="hd_h_ml114.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Maybridge</td><td headers="hd_h_ml114.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CD 11516</td><td headers="hd_h_ml114.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2806061</td><td headers="hd_h_ml114.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85857710" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85857710</a></td><td headers="hd_h_ml114.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">-</td><td headers="hd_h_ml114.t2_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">See below <sup><a class="bk_pop" href="#ml114.tfn12">*</a></sup></td><td headers="hd_h_ml114.t2_1_1_1_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td><td headers="hd_h_ml114.t2_1_1_1_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NT</td></tr><tr><td headers="hd_h_ml114.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">14</td><td headers="hd_h_ml114.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50690/bin/ml114fu24.jpg" alt="Image ml114fu24.jpg" /></div></td><td headers="hd_h_ml114.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">DAB/MW</td><td headers="hd_h_ml114.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MW-I-45</td><td headers="hd_h_ml114.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">44521938</td><td headers="hd_h_ml114.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85857715" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85857715</a></td><td headers="hd_h_ml114.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">-</td><td headers="hd_h_ml114.t2_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">See below<sup><a class="bk_pop" href="#ml114.tfn12">*</a></sup></td><td headers="hd_h_ml114.t2_1_1_1_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">42</td><td headers="hd_h_ml114.t2_1_1_1_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td></tr><tr><td headers="hd_h_ml114.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">15</td><td headers="hd_h_ml114.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50690/bin/ml114fu25.jpg" alt="Image ml114fu25.jpg" /></div></td><td headers="hd_h_ml114.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">DAB</td><td headers="hd_h_ml114.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">DAB-IV- 40</td><td headers="hd_h_ml114.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">44521939</td><td headers="hd_h_ml114.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85857716" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85857716</a></td><td headers="hd_h_ml114.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">-</td><td headers="hd_h_ml114.t2_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">See below<sup><a class="bk_pop" href="#ml114.tfn12">*</a></sup></td><td headers="hd_h_ml114.t2_1_1_1_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td><td headers="hd_h_ml114.t2_1_1_1_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NT</td></tr><tr><td headers="hd_h_ml114.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">16</td><td headers="hd_h_ml114.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50690/bin/ml114fu26.jpg" alt="Image ml114fu26.jpg" /></div></td><td headers="hd_h_ml114.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Key Organics</td><td headers="hd_h_ml114.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">9w-0871</td><td headers="hd_h_ml114.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">9655388</td><td headers="hd_h_ml114.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/25817285" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">25817285</a></td><td headers="hd_h_ml114.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">-</td><td headers="hd_h_ml114.t2_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">See below<sup><a class="bk_pop" href="#ml114.tfn12">*</a></sup></td><td headers="hd_h_ml114.t2_1_1_1_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">17</td><td headers="hd_h_ml114.t2_1_1_1_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td></tr><tr><td headers="hd_h_ml114.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">17</td><td headers="hd_h_ml114.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50690/bin/ml114fu27.jpg" alt="Image ml114fu27.jpg" /></div></td><td headers="hd_h_ml114.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Key Organics</td><td headers="hd_h_ml114.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">9w-0873</td><td headers="hd_h_ml114.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">9638786</td><td headers="hd_h_ml114.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/25817287" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">25817287</a></td><td headers="hd_h_ml114.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">-</td><td headers="hd_h_ml114.t2_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">See below<sup><a class="bk_pop" href="#ml114.tfn12">*</a></sup></td><td headers="hd_h_ml114.t2_1_1_1_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">14</td><td headers="hd_h_ml114.t2_1_1_1_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NT</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>*</dt><dd><div id="ml114.tfn12"><p class="no_margin">These compounds were not tested in ABPP dose response assays because they were less selective than the lead compound as determined using the Gel-based ABPP Inhibition assay.</p></div></dd><dt>□</dt><dd><div id="ml114.tfn13"><p class="no_margin">Anti-targets: ≥ 50 inhibition observed at 20µM compound concentration (mouse brain membrane proteome, 1mg/mL)</p></div></dd></dl></div></div></div><div id="ml114.f1" class="figure bk_fig"><div class="graphic"><img src="/books/NBK50690/bin/ml114f1.jpg" alt="Figure A2.1. Low throughput assays to characterize probe." /></div><h3><span class="label">Figure A2.1</span><span class="title">Low throughput assays to characterize probe</span></h3><div class="caption"><p><b>a.</b> Selective inhibition of
|
||
exogenous RBBP9 doped into the mouse brain membrane proteome by oxime ester compounds as determined
|
||
by gel-based ABPP. <b>b.</b> Unlike emetine, compound <b>1</b> covalently inhibits
|
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RBBP9, retaining inhibitory activity after gel filtration. <b>c.</b> Identification of the
|
||
acyl-enzyme adduct of compound <b>1</b> by mass spectrometry. <b>d</b>. (next page) Compound selectivity at 20 µM in mouse brain proteome. a, b (top), and d: fluorescent image of SDS-PAGE gels shown in grey scale. Compound numbers refer to their entry numbers in <a class="figpopup" href="/books/NBK50690/table/ml114.t3/?report=objectonly" target="object" rid-figpopup="figml114t3" rid-ob="figobml114t3">Table A2.1</a></p></div></div><div id="ml114.f2" class="figure bk_fig"><div class="graphic"><img src="/books/NBK50690/bin/ml114f2.jpg" alt="Figure A2.2. Cytotoxicity of RBBP9 inhibitors against HEK 293T cells after 48h of treatment as determined by the CellTiter-Glo assay (Promega)." /></div><h3><span class="label">Figure A2.2</span><span class="title">Cytotoxicity of RBBP9 inhibitors against HEK 293T cells after 48h of treatment as determined
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||
by the CellTiter-Glo assay (Promega)</span></h3><div class="caption"><p>Emetine is highly cytotoxic (CC<sub>50</sub><100
|
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nM), but the oxime ester compounds, including the probe compound, exhibited no toxicity (CC<sub>50</sub>>100 μM) at compound concentrations tested. Compound numbers refer to their entry numbers in <a class="figpopup" href="/books/NBK50690/table/ml114.t3/?report=objectonly" target="object" rid-figpopup="figml114t3" rid-ob="figobml114t3">Tables 1</a> and <a class="figpopup" href="/books/NBK50690/table/ml114.t4/?report=objectonly" target="object" rid-figpopup="figml114t4" rid-ob="figobml114t4">2</a></p></div></div><div id="ml114.f3" class="figure bk_fig"><div class="graphic"><img src="/books/NBK50690/bin/ml114f3.jpg" alt="Figure A2.3. Stability of ML114 (Compound 1) in PBS indicates a half-life of 45 hours." /></div><h3><span class="label">Figure A2.3</span><span class="title">Stability of <a href="/pcsubstance/?term=ML114[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML114</a> (Compound 1) in PBS indicates a half-life of 45 hours</span></h3></div></div><div id="ml114.s33"><h3>Appendix 3. Supplemental SAR Tables</h3><div id="ml114.t3" class="table"><h3><span class="label">Table A3.1</span><span class="title">Additional oxime ester SAR, including analogs of oxime ester <b>18</b> (CID 885318)</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK50690/table/ml114.t3/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml114.t3_lrgtbl__"><table class="no_margin"><thead><tr><th id="hd_h_ml114.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Entry</th><th id="hd_h_ml114.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Structure</th><th id="hd_h_ml114.t3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Vendor or Chemist</th><th id="hd_h_ml114.t3_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Catalog Number</th><th id="hd_h_ml114.t3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">PubChem CID</th><th id="hd_h_ml114.t3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">PubChem SID</th><th id="hd_h_ml114.t3_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">ABPP IC<sub>50</sub> μM)</th><th id="hd_h_ml114.t3_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">% Inhibition (20 μM)</th><th id="hd_h_ml114.t3_1_1_1_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Anti- targets<sup><a class="bk_pop" href="#ml114.tfn15">□</a></sup> (20 μM)</th></tr></thead><tbody><tr><td headers="hd_h_ml114.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">18</td><td headers="hd_h_ml114.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><div class="graphic"><img src="/books/NBK50690/bin/ml114fu28.jpg" alt="Image ml114fu28.jpg" /></div></td><td headers="hd_h_ml114.t3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">ChemBridge</td><td headers="hd_h_ml114.t3_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">6625888</td><td headers="hd_h_ml114.t3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">885318</td><td headers="hd_h_ml114.t3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/17414090" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">17414090</a></td><td headers="hd_h_ml114.t3_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1.2</td><td headers="hd_h_ml114.t3_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">78</td><td headers="hd_h_ml114.t3_1_1_1_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NT</td></tr><tr><td headers="hd_h_ml114.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">19</td><td headers="hd_h_ml114.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><div class="graphic"><img src="/books/NBK50690/bin/ml114fu29.jpg" alt="Image ml114fu29.jpg" /></div></td><td headers="hd_h_ml114.t3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">ChemBridge</td><td headers="hd_h_ml114.t3_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">7195982</td><td headers="hd_h_ml114.t3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">710899</td><td headers="hd_h_ml114.t3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/3554491" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">3554491</a></td><td headers="hd_h_ml114.t3_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1.5</td><td headers="hd_h_ml114.t3_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">93</td><td headers="hd_h_ml114.t3_1_1_1_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml114.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">20</td><td headers="hd_h_ml114.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><div class="graphic"><img src="/books/NBK50690/bin/ml114fu30.jpg" alt="Image ml114fu30.jpg" /></div></td><td headers="hd_h_ml114.t3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">ChemBridge</td><td headers="hd_h_ml114.t3_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">7123758</td><td headers="hd_h_ml114.t3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">710852</td><td headers="hd_h_ml114.t3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85857709" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85857709</a></td><td headers="hd_h_ml114.t3_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">See below<sup><a class="bk_pop" href="#ml114.tfn14">*</a></sup></td><td headers="hd_h_ml114.t3_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">76</td><td headers="hd_h_ml114.t3_1_1_1_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml114.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">21</td><td headers="hd_h_ml114.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><div class="graphic"><img src="/books/NBK50690/bin/ml114fu31.jpg" alt="Image ml114fu31.jpg" /></div></td><td headers="hd_h_ml114.t3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">ChemBridge</td><td headers="hd_h_ml114.t3_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">6628850</td><td headers="hd_h_ml114.t3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">776177</td><td headers="hd_h_ml114.t3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/3493187" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">3493187</a></td><td headers="hd_h_ml114.t3_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">See below<sup><a class="bk_pop" href="#ml114.tfn14">*</a></sup></td><td headers="hd_h_ml114.t3_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">48</td><td headers="hd_h_ml114.t3_1_1_1_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml114.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">22</td><td headers="hd_h_ml114.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><div class="graphic"><img src="/books/NBK50690/bin/ml114fu32.jpg" alt="Image ml114fu32.jpg" /></div></td><td headers="hd_h_ml114.t3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">DAB/MW</td><td headers="hd_h_ml114.t3_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">MW-I-50</td><td headers="hd_h_ml114.t3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">44521941</td><td headers="hd_h_ml114.t3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85857717" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85857717</a></td><td headers="hd_h_ml114.t3_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">See below<sup><a class="bk_pop" href="#ml114.tfn14">*</a></sup></td><td headers="hd_h_ml114.t3_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">42</td><td headers="hd_h_ml114.t3_1_1_1_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NT</td></tr><tr><td headers="hd_h_ml114.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">23</td><td headers="hd_h_ml114.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><div class="graphic"><img src="/books/NBK50690/bin/ml114fu33.jpg" alt="Image ml114fu33.jpg" /></div></td><td headers="hd_h_ml114.t3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">ChemBridge</td><td headers="hd_h_ml114.t3_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">5330467</td><td headers="hd_h_ml114.t3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2841783</td><td headers="hd_h_ml114.t3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85857711" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85857711</a></td><td headers="hd_h_ml114.t3_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">See below<sup><a class="bk_pop" href="#ml114.tfn14">*</a></sup></td><td headers="hd_h_ml114.t3_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">5</td><td headers="hd_h_ml114.t3_1_1_1_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml114.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">24</td><td headers="hd_h_ml114.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><div class="graphic"><img src="/books/NBK50690/bin/ml114fu34.jpg" alt="Image ml114fu34.jpg" /></div></td><td headers="hd_h_ml114.t3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">ChemBridge</td><td headers="hd_h_ml114.t3_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">6151656</td><td headers="hd_h_ml114.t3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2887848</td><td headers="hd_h_ml114.t3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85857708" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85857708</a></td><td headers="hd_h_ml114.t3_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">See below<sup><a class="bk_pop" href="#ml114.tfn14">*</a></sup></td><td headers="hd_h_ml114.t3_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td><td headers="hd_h_ml114.t3_1_1_1_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml114.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">25</td><td headers="hd_h_ml114.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><div class="graphic"><img src="/books/NBK50690/bin/ml114fu35.jpg" alt="Image ml114fu35.jpg" /></div></td><td headers="hd_h_ml114.t3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">ChemBridge</td><td headers="hd_h_ml114.t3_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">6575017</td><td headers="hd_h_ml114.t3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">5730927</td><td headers="hd_h_ml114.t3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85857712" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85857712</a></td><td headers="hd_h_ml114.t3_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">See below<sup><a class="bk_pop" href="#ml114.tfn14">*</a></sup></td><td headers="hd_h_ml114.t3_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">6</td><td headers="hd_h_ml114.t3_1_1_1_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml114.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">26</td><td headers="hd_h_ml114.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><div class="graphic"><img src="/books/NBK50690/bin/ml114fu36.jpg" alt="Image ml114fu36.jpg" /></div></td><td headers="hd_h_ml114.t3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">ChemBridge</td><td headers="hd_h_ml114.t3_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">6576173</td><td headers="hd_h_ml114.t3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">5730966</td><td headers="hd_h_ml114.t3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85857713" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85857713</a></td><td headers="hd_h_ml114.t3_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">See below<sup><a class="bk_pop" href="#ml114.tfn14">*</a></sup></td><td headers="hd_h_ml114.t3_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">28</td><td headers="hd_h_ml114.t3_1_1_1_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>*</dt><dd><div id="ml114.tfn14"><p class="no_margin">These compounds were not tested in ABPP dose response assays because they were less selective than the lead compound, as determined using the Gel-based ABPP Inhibition assay.</p></div></dd><dt>□</dt><dd><div id="ml114.tfn15"><p class="no_margin">Anti-targets: ≥ 50 inhibition observed at 20µM compound concentration (mouse brain membrane proteome, 1mg/mL)</p></div></dd></dl></div></div></div><div id="ml114.t4" class="table"><h3><span class="label">Table A3.2</span><span class="title">Initial round of SAR by purchase with large structural modifications</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK50690/table/ml114.t4/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml114.t4_lrgtbl__"><table class="no_margin"><thead><tr><th id="hd_h_ml114.t4_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Number</th><th id="hd_h_ml114.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Structure</th><th id="hd_h_ml114.t4_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Vendor</th><th id="hd_h_ml114.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Catalog Number</th><th id="hd_h_ml114.t4_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">PubChem CID</th><th id="hd_h_ml114.t4_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">PubChem SID</th><th id="hd_h_ml114.t4_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">% Inhibition (20 μM)</th><th id="hd_h_ml114.t4_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Anti- targets<sup><a class="bk_pop" href="#ml114.tfn16">□</a></sup> (20 μM)</th></tr></thead><tbody><tr><td headers="hd_h_ml114.t4_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">27</td><td headers="hd_h_ml114.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50690/bin/ml114fu37.jpg" alt="Image ml114fu37.jpg" /></div></td><td headers="hd_h_ml114.t4_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Enamine</td><td headers="hd_h_ml114.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">T0502-2638</td><td headers="hd_h_ml114.t4_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5410001</td><td headers="hd_h_ml114.t4_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/25051074" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">25051074</a></td><td headers="hd_h_ml114.t4_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td><td headers="hd_h_ml114.t4_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td></tr><tr><td headers="hd_h_ml114.t4_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">28</td><td headers="hd_h_ml114.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50690/bin/ml114fu38.jpg" alt="Image ml114fu38.jpg" /></div></td><td headers="hd_h_ml114.t4_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Enamine</td><td headers="hd_h_ml114.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">T0502-2646</td><td headers="hd_h_ml114.t4_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6948141</td><td headers="hd_h_ml114.t4_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/25051081" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">25051081</a></td><td headers="hd_h_ml114.t4_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td><td headers="hd_h_ml114.t4_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NT</td></tr><tr><td headers="hd_h_ml114.t4_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">29</td><td headers="hd_h_ml114.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50690/bin/ml114fu39.jpg" alt="Image ml114fu39.jpg" /></div></td><td headers="hd_h_ml114.t4_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Enamine</td><td headers="hd_h_ml114.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">T0503-6530</td><td headers="hd_h_ml114.t4_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5862509</td><td headers="hd_h_ml114.t4_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/25086175" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">25086175</a></td><td headers="hd_h_ml114.t4_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">57</td><td headers="hd_h_ml114.t4_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">FAAH</td></tr><tr><td headers="hd_h_ml114.t4_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">30</td><td headers="hd_h_ml114.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50690/bin/ml114fu40.jpg" alt="Image ml114fu40.jpg" /></div></td><td headers="hd_h_ml114.t4_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Enamine</td><td headers="hd_h_ml114.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">T0503-8825</td><td headers="hd_h_ml114.t4_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5884610</td><td headers="hd_h_ml114.t4_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/25060406" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">25060406</a></td><td headers="hd_h_ml114.t4_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td><td headers="hd_h_ml114.t4_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">FAAH</td></tr><tr><td headers="hd_h_ml114.t4_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">31</td><td headers="hd_h_ml114.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50690/bin/ml114fu41.jpg" alt="Image ml114fu41.jpg" /></div></td><td headers="hd_h_ml114.t4_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Enamine</td><td headers="hd_h_ml114.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">T0504-3259</td><td headers="hd_h_ml114.t4_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">44521940</td><td headers="hd_h_ml114.t4_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85857714" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85857714</a></td><td headers="hd_h_ml114.t4_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td><td headers="hd_h_ml114.t4_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td></tr><tr><td headers="hd_h_ml114.t4_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">32</td><td headers="hd_h_ml114.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50690/bin/ml114fu42.jpg" alt="Image ml114fu42.jpg" /></div></td><td headers="hd_h_ml114.t4_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Enamine</td><td headers="hd_h_ml114.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">T0510-1157</td><td headers="hd_h_ml114.t4_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5759308</td><td headers="hd_h_ml114.t4_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/25101467" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">25101467</a></td><td headers="hd_h_ml114.t4_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td><td headers="hd_h_ml114.t4_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td></tr><tr><td headers="hd_h_ml114.t4_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">33</td><td headers="hd_h_ml114.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50690/bin/ml114fu43.jpg" alt="Image ml114fu43.jpg" /></div></td><td headers="hd_h_ml114.t4_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Enamine</td><td headers="hd_h_ml114.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">T0511-0232</td><td headers="hd_h_ml114.t4_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5848571</td><td headers="hd_h_ml114.t4_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/25093682" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">25093682</a></td><td headers="hd_h_ml114.t4_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">10</td><td headers="hd_h_ml114.t4_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td></tr><tr><td headers="hd_h_ml114.t4_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">34</td><td headers="hd_h_ml114.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50690/bin/ml114fu44.jpg" alt="Image ml114fu44.jpg" /></div></td><td headers="hd_h_ml114.t4_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Enamine</td><td headers="hd_h_ml114.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">T0516-6046</td><td headers="hd_h_ml114.t4_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4622685</td><td headers="hd_h_ml114.t4_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/25183312" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">25183312</a></td><td headers="hd_h_ml114.t4_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td><td headers="hd_h_ml114.t4_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td></tr><tr><td headers="hd_h_ml114.t4_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">35</td><td headers="hd_h_ml114.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50690/bin/ml114fu45.jpg" alt="Image ml114fu45.jpg" /></div></td><td headers="hd_h_ml114.t4_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Enamine</td><td headers="hd_h_ml114.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">T0517-8591</td><td headers="hd_h_ml114.t4_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3591160</td><td headers="hd_h_ml114.t4_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/25172978" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">25172978</a></td><td headers="hd_h_ml114.t4_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td><td headers="hd_h_ml114.t4_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td></tr><tr><td headers="hd_h_ml114.t4_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">36</td><td headers="hd_h_ml114.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50690/bin/ml114fu46.jpg" alt="Image ml114fu46.jpg" /></div></td><td headers="hd_h_ml114.t4_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Enamine</td><td headers="hd_h_ml114.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">T5300364</td><td headers="hd_h_ml114.t4_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">9569263</td><td headers="hd_h_ml114.t4_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/25285852" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">25285852</a></td><td headers="hd_h_ml114.t4_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td><td headers="hd_h_ml114.t4_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td></tr><tr><td headers="hd_h_ml114.t4_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">37</td><td headers="hd_h_ml114.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50690/bin/ml114fu47.jpg" alt="Image ml114fu47.jpg" /></div></td><td headers="hd_h_ml114.t4_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Enamine</td><td headers="hd_h_ml114.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">T5786209</td><td headers="hd_h_ml114.t4_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">17558189</td><td headers="hd_h_ml114.t4_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/28310332" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">28310332</a></td><td headers="hd_h_ml114.t4_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">15</td><td headers="hd_h_ml114.t4_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>□</dt><dd><div id="ml114.tfn16"><p class="no_margin">Anti-targets: ≥ 50 inhibition observed at 20µM compound concentration (mouse brain membrane proteome, 1mg/mL)</p></div></dd></dl></div></div></div></div></div><div id="ml114.s34"><h2 id="_ml114_s34_">5. References</h2><dl class="temp-labeled-list"><dt>1.</dt><dd><div class="bk_ref" id="ml114.r1">Nevins JR. E2F: a link between the Rb tumor suppressor protein and viral oncoproteins. <span><span class="ref-journal">Science. </span>1992;<span class="ref-vol">258</span>(5081):424–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/1411535" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 1411535</span></a>]</div></dd><dt>2.</dt><dd><div class="bk_ref" id="ml114.r2">Chen JZ, Yang QS, Wang S, Meng XF, Ying K, Xie Y, Ma YM. Cloning and expression of a novel retinoblastoma binding protein cDNA, RBBP10. <span><span class="ref-journal">Biochem Genet. </span>2002;<span class="ref-vol">40</span>:7–8. 273–82.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12296629" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12296629</span></a>]</div></dd><dt>3.</dt><dd><div class="bk_ref" id="ml114.r3">Woitach JT, Zhang M, Niu CH, Thorgeirsson SS. A retinoblastoma-binding protein that affects cell-cycle control and confers transforming ability. <span><span class="ref-journal">Nat Genet. </span>1998;<span class="ref-vol">19</span>(4):371–4.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9697699" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9697699</span></a>]</div></dd><dt>4.</dt><dd><div class="bk_ref" id="ml114.r4">Vorobiev SM, Su M, Seetharaman J, Huang YJ, Chen CX, Maglaqui M, Janjua H, Proudfoot M, Yakunin A, Xiao R, Acton TB, Montelione GT, Tong L. Crystal structure of human retinoblastoma binding protein 9. <span><span class="ref-journal">Proteins. </span>2009;<span class="ref-vol">74</span>(2):526–9.</span> [<a href="/pmc/articles/PMC2684859/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2684859</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19004028" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19004028</span></a>]</div></dd><dt>5.</dt><dd><div class="bk_ref" id="ml114.r5">Woitach JT, Hong R, Keck CL, Zimonjic DB, Popescu NC, Thorgeirsson SS. Assignment of the Bog gene (RBBP9) to syntenic regions of mouse chromosome 2G1-H1 and human chromosome 20p11.2 by fluorescence in situ hybridization. <span><span class="ref-journal">Cytogenet Cell Genet. </span>1999;<span class="ref-vol">85</span>:3–4. 252–3.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/10449909" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10449909</span></a>]</div></dd><dt>6.</dt><dd><div class="bk_ref" id="ml114.r6">Cassie S, Koturbash I, Hudson D, Baker M, Ilnytskyy Y, Rodriguez-Juarez R, Weber E, Kovalchuk O. Novel retinoblastoma binding protein RBBP9 modulates sex-specific radiation responses in vivo. <span><span class="ref-journal">Carcinogenesis. </span>2006;<span class="ref-vol">27</span>(3):465–74.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16272168" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16272168</span></a>]</div></dd><dt>7.</dt><dd><div class="bk_ref" id="ml114.r7">Jessani N, et al. Enzyme activity profiles of the secreted and membrane proteome that depict cancer cell invasiveness. <span><span class="ref-journal">Proc Natl Acad Sci U S A. </span>2002;<span class="ref-vol">99</span>(16):10335–40.</span> [<a href="/pmc/articles/PMC124915/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC124915</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/12149457" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12149457</span></a>]</div></dd><dt>8.</dt><dd><div class="bk_ref" id="ml114.r8">Leung D, et al. Discovering potent and selective reversible inhibitors of enzymes in complex proteomes. <span><span class="ref-journal">Nat Biotechnol. </span>2003;<span class="ref-vol">21</span>(6):687–91.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12740587" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12740587</span></a>]</div></dd><dt>9.</dt><dd><div class="bk_ref" id="ml114.r9">Bachovchin DA, et al. Identification of selective inhibitors of uncharacterized enzymes by high-throughput screening with fluorescent activity-based probes. <span><span class="ref-journal">Nat Biotechnol. </span>2009;<span class="ref-vol">27</span>(4):387–94.</span> [<a href="/pmc/articles/PMC2709489/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2709489</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19329999" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19329999</span></a>]</div></dd><dt>10.</dt><dd><div class="bk_ref" id="ml114.r10">Johnson DS, Weerapana E, Cravatt BF. Strategies for discovering and derisking covalent, irreversible enzyme inhibitors. <span><span class="ref-journal">Future Med Chem. </span>2010;<span class="ref-vol">2</span>(6):949–964.</span> [<a href="/pmc/articles/PMC2904065/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2904065</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20640225" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20640225</span></a>]</div></dd><dt>11.</dt><dd><div class="bk_ref" id="ml114.r11">Vincent PW, et al. Anticancer efficacy of the irreversible EGFr tyrosine kinase inhibitor PD 0169414 against human tumor xenografts. <span><span class="ref-journal">Cancer Chemother Pharmacol. </span>2000;<span class="ref-vol">45</span>(3):231–8.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/10663641" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10663641</span></a>]</div></dd><dt>12.</dt><dd><div class="bk_ref" id="ml114.r12">Robertson JG. Mechanistic basis of enzyme-targeted drugs. <span><span class="ref-journal">Biochemistry. </span>2005;<span class="ref-vol">44</span>(15):5561–71.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15823014" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15823014</span></a>]</div></dd><dt>13.</dt><dd><div class="bk_ref" id="ml114.r13">Egan WJ, Merz KM Jr, Baldwin JJ. Prediction of drug absorption using multivariate statistics. <span><span class="ref-journal">J Med Chem. </span>2000;<span class="ref-vol">43</span>:3867–3877.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11052792" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11052792</span></a>]</div></dd><dt>14.</dt><dd><div class="bk_ref" id="ml114.r14">Egan WJ, Lauri G. Prediction of intestinal permeability. <span><span class="ref-journal">Adv Drug Deliv Rev. </span>2002;<span class="ref-vol">54</span>:273–289.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11922948" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11922948</span></a>]</div></dd></dl></div><div style="display:none"><div style="display:none" id="figml114f1"><img alt="Image ml114f1" src-large="/books/NBK50690/bin/ml114f1.jpg" /></div><div style="display:none" id="figml114f2"><img alt="Image ml114f2" src-large="/books/NBK50690/bin/ml114f2.jpg" /></div><div style="display:none" id="figml114f3"><img alt="Image ml114f3" src-large="/books/NBK50690/bin/ml114f3.jpg" /></div></div><div id="bk_toc_contnr"></div></div></div>
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<div xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Views</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="PDF_download" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="/books/NBK50690/?report=reader">PubReader</a></li><li><a href="/books/NBK50690/?report=printable">Print View</a></li><li><a data-jig="ncbidialog" href="#_ncbi_dlg_citbx_NBK50690" data-jigconfig="width:400,modal:true">Cite this Page</a><div id="_ncbi_dlg_citbx_NBK50690" style="display:none" title="Cite this Page"><div class="bk_tt">Bachovchin DA, Speers AE, Brown SJ, et al. Probe Report for RBBP9 Inhibitors - Probe 2. 2009 Aug 20 [Updated 2010 Oct 20]. 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></div></div></li><li><a href="/books/NBK50690/pdf/Bookshelf_NBK50690.pdf">PDF version of this page</a> (582K)</li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>In this Page</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="page-toc" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="#ml114.s2" ref="log$=inpage&link_id=inpage">Probe Structure & Characteristics and Prior Art</a></li><li><a href="#ml114.s3" ref="log$=inpage&link_id=inpage">Probe Selection</a></li><li><a href="#ml114.s4" ref="log$=inpage&link_id=inpage">Recommendations for the Scientific Use of This Probe</a></li><li><a href="#ml114.s5" ref="log$=inpage&link_id=inpage">Scientific Rationale for Project</a></li><li><a href="#ml114.s6" ref="log$=inpage&link_id=inpage">Project Description</a></li><li><a href="#ml114.s16" ref="log$=inpage&link_id=inpage">Probe</a></li><li><a href="#ml114.s30" ref="log$=inpage&link_id=inpage">Appendices</a></li><li><a href="#ml114.s34" ref="log$=inpage&link_id=inpage">References</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Related information</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="discovery_db_links" id="Shutter"></a></div><div class="portlet_content"><ul><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pmc&DbFrom=books&Cmd=Link&LinkName=books_pmc_refs&IdsFromResult=2376686" ref="log$=recordlinks">PMC</a><div class="brieflinkpop offscreen_noflow">PubMed Central citations</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pcassay&DbFrom=books&Cmd=Link&LinkName=books_pcassay_probe&IdsFromResult=2376686" ref="log$=recordlinks">PubChem BioAssay for Chemical Probe</a><div class="brieflinkpop offscreen_noflow">PubChem BioAssay records reporting screening data for the development of the chemical probe(s) described in this book chapter</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pcsubstance&DbFrom=books&Cmd=Link&LinkName=books_pcsubstance&IdsFromResult=2376686" ref="log$=recordlinks">PubChem Substance</a><div class="brieflinkpop offscreen_noflow">Related PubChem Substances</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pubmed&DbFrom=books&Cmd=Link&LinkName=books_pubmed_refs&IdsFromResult=2376686" ref="log$=recordlinks">PubMed</a><div class="brieflinkpop offscreen_noflow">Links to PubMed</div></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Similar articles in PubMed</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="PBooksDiscovery_RA" id="Shutter"></a></div><div class="portlet_content"><ul><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/21433353" ref="ordinalpos=1&linkpos=1&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Probe Report for RBBP9 Inhibitors - 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Epub 2005 Nov 4.</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/12670895" ref="ordinalpos=1&linkpos=4&log$=relatedarticles&logdbfrom=pubmed">An oncolytic adenovirus selective for retinoblastoma tumor suppressor protein pathway-defective tumors: dependence on E1A, the E2F-1 promoter, and viral replication for selectivity and efficacy.</a><span class="source">[Cancer Res. 2003]</span><div class="brieflinkpop offscreen_noflow">An oncolytic adenovirus selective for retinoblastoma tumor suppressor protein pathway-defective tumors: dependence on E1A, the E2F-1 promoter, and viral replication for selectivity and efficacy.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Jakubczak JL, Ryan P, Gorziglia M, Clarke L, Hawkins LK, Hay C, Huang Y, Kaloss M, Marinov A, Phipps S, et al. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">Cancer Res. 2003 Apr 1; 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