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<script type="text/javascript" src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.boots.min.js"> </script><title>Small-Molecule Inhibitors of Vaccinia-H1-Related Phosphatase VHR - Probe Reports from the NIH Molecular Libraries Program - NCBI Bookshelf</title>
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<meta name="citation_inbook_title" content="Probe Reports from the NIH Molecular Libraries Program [Internet]">
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<meta name="citation_title" content="Small-Molecule Inhibitors of Vaccinia-H1-Related Phosphatase VHR">
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<meta name="citation_publisher" content="National Center for Biotechnology Information (US)">
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<meta name="citation_date" content="2010/10/04">
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<meta name="citation_author" content="Lutz Tautz">
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<meta name="citation_author" content="Tomas Mustelin">
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<meta name="citation_author" content="Shuangding Wu">
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<meta name="citation_author" content="Sofie Vossius">
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<meta name="citation_author" content="Souad Rahmouni">
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<meta name="citation_author" content="Stefan Vasile">
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<meta name="citation_author" content="Eduard Sergienko">
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<meta name="citation_author" content="Derek Stonich">
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<meta name="citation_author" content="Hongbin Yuan">
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<meta name="citation_author" content="Ying Su">
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<meta name="citation_author" content="Russell Dahl">
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<meta name="citation_author" content="Yalda Mostofi">
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<meta name="citation_author" content="Thomas DY Chung">
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<meta name="citation_pmid" content="21433385">
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<meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK50693/">
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<meta name="DC.Title" content="Small-Molecule Inhibitors of Vaccinia-H1-Related Phosphatase VHR">
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<meta name="DC.Type" content="Text">
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<meta name="DC.Publisher" content="National Center for Biotechnology Information (US)">
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<meta name="DC.Contributor" content="Lutz Tautz">
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<meta name="DC.Contributor" content="Tomas Mustelin">
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<meta name="DC.Contributor" content="Shuangding Wu">
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<meta name="DC.Contributor" content="Sofie Vossius">
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<meta name="DC.Contributor" content="Souad Rahmouni">
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<meta name="DC.Contributor" content="Stefan Vasile">
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<meta name="DC.Contributor" content="Eduard Sergienko">
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<meta name="DC.Contributor" content="Derek Stonich">
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<meta name="DC.Contributor" content="Hongbin Yuan">
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<meta name="DC.Contributor" content="Ying Su">
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<meta name="DC.Contributor" content="Russell Dahl">
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<meta name="DC.Contributor" content="Yalda Mostofi">
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<meta name="DC.Contributor" content="Thomas DY Chung">
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<meta name="DC.Date" content="2010/10/04">
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<meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK50693/">
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<meta name="description" content="Vaccinia H1-related (VHR) protein tyrosine phosphatase dephosphorylates and thereby inactivates extracellular signal-regulated kinases Erk1/2 and c-Jun N-terminal kinases Jnk1/2. These mitogen-activated protein (MAP) kinases mediate major signaling pathways triggered by extracellular growth factor, stress, or cytokines and regulate cellular processes such as differentiation, proliferation and apoptosis. Unlike many MAP kinase phosphatases (MKPs), VHR expression is not induced in response to activation of MAP kinases, but is instead regulated during cell cycle progression. The loss of VHR causes cell cycle arrest in HeLa carcinoma cells, suggesting that VHR inhibition may be a useful approach to halt the growth of cancer cells without detrimental effects on normal cells. Here we report the development of multidentate small-molecule inhibitors of VHR that inhibit its enzymatic activity at nanomolar concentrations and are selective for VHR over HePTP and MKP-1. This novel small molecular probe, ML113 (CID-6161281) appears to interact with both the phosphate-binding pocket and several distinct hydrophobic regions within VHR's active site. As a result, it will serve as a useful tool in probing these interactions and elucidating the molecular mechanism underlying the selectivity against this phosphatase, in addition to providing greater understanding of the functional consequences for cancer biology.">
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<meta name="og:description" content="Vaccinia H1-related (VHR) protein tyrosine phosphatase dephosphorylates and thereby inactivates extracellular signal-regulated kinases Erk1/2 and c-Jun N-terminal kinases Jnk1/2. These mitogen-activated protein (MAP) kinases mediate major signaling pathways triggered by extracellular growth factor, stress, or cytokines and regulate cellular processes such as differentiation, proliferation and apoptosis. Unlike many MAP kinase phosphatases (MKPs), VHR expression is not induced in response to activation of MAP kinases, but is instead regulated during cell cycle progression. The loss of VHR causes cell cycle arrest in HeLa carcinoma cells, suggesting that VHR inhibition may be a useful approach to halt the growth of cancer cells without detrimental effects on normal cells. Here we report the development of multidentate small-molecule inhibitors of VHR that inhibit its enzymatic activity at nanomolar concentrations and are selective for VHR over HePTP and MKP-1. This novel small molecular probe, ML113 (CID-6161281) appears to interact with both the phosphate-binding pocket and several distinct hydrophobic regions within VHR's active site. As a result, it will serve as a useful tool in probing these interactions and elucidating the molecular mechanism underlying the selectivity against this phosphatase, in addition to providing greater understanding of the functional consequences for cancer biology.">
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id="jr-fip-info-p"><a id="jr-fip-prev" class="wsprkl btn" title="Jump to previuos match">◀</a><button id="jr-fip-matches">no matches yet</button><a id="jr-fip-next" class="wsprkl btn" title="Jump to next match">▶</a></nav></nav></div><div id="jr-epub-interstitial" class="hidden"></div><div id="jr-content"><article data-type="main"><div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><div class="fm-sec"><h1 id="_NBK50693_"><span class="title" itemprop="name">Small-Molecule Inhibitors of Vaccinia-H1-Related Phosphatase VHR</span></h1><p class="contribs">Tautz L, Mustelin T, Wu S, et al.</p><p class="fm-aai"><a href="#_NBK50693_pubdet_">Publication Details</a></p></div></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="_abs_rndgid_" itemprop="description"><p>Vaccinia H1-related (VHR) protein tyrosine phosphatase dephosphorylates and thereby inactivates extracellular signal-regulated kinases Erk1/2 and c-Jun N-terminal kinases Jnk1/2. These mitogen-activated protein (MAP) kinases mediate major signaling pathways triggered by extracellular growth factor, stress, or cytokines and regulate cellular processes such as differentiation, proliferation and apoptosis. Unlike many MAP kinase phosphatases (MKPs), VHR expression is not induced in response to activation of MAP kinases, but is instead regulated during cell cycle progression. The loss of VHR causes cell cycle arrest in HeLa carcinoma cells, suggesting that VHR inhibition may be a useful approach to halt the growth of cancer cells without detrimental effects on normal cells. Here we report the development of multidentate small-molecule inhibitors of VHR that inhibit its enzymatic activity at nanomolar concentrations and are selective for VHR over HePTP and MKP-1. This novel small molecular probe, ML113 (CID-6161281) appears to interact with both the phosphate-binding pocket and several distinct hydrophobic regions within VHR's active site. As a result, it will serve as a useful tool in probing these interactions and elucidating the molecular mechanism underlying the selectivity against this phosphatase, in addition to providing greater understanding of the functional consequences for cancer biology.</p></div><div class="h2"></div><p><b>Assigned Assay Grant #:</b> 1 R03 MH084230-01A1</p><p><b>Screening Center Name & PI:</b> Burnham Center for Chemical Genomics & Dr John C Reed</p><p><b>Chemistry Center Name & PI:</b> Burnham Center for Chemical Genomics & Dr John C Reed</p><p><b>Assay Submitter & Institution:</b> Lutz Tautz & Burnham Institute for Medical Research</p><p><b>PubChem Summary Bioassay Identifier (AID):</b>
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<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1661" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1661</a></p><div id="ml113.s2"><h2 id="_ml113_s2_">Probe Structure & Characteristics</h2><p>CID-6161281</p><p>(Cmpd internal # is MLS-0425632)</p><div id="ml113.fu1" class="figure"><div class="graphic"><img src="/books/NBK50693/bin/ml113fu1.jpg" alt="Image ml113fu1" /></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml113tu1"><a href="/books/NBK50693/table/ml113.tu1/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figml113tu1" rid-ob="figobml113tu1"><img class="small-thumb" src="/books/NBK50693/table/ml113.tu1/?report=thumb" src-large="/books/NBK50693/table/ml113.tu1/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ml113.tu1"><a href="/books/NBK50693/table/ml113.tu1/?report=objectonly" target="object" rid-ob="figobml113tu1">Table</a></h4></div></div></div><div id="ml113.s3"><h2 id="_ml113_s3_">Recommendations for the scientific use of this probe</h2><p>Loss of VHR phosphatase causes cell cycle arrest in HeLa carcinoma cells, suggesting that VHR inhibition may be a useful approach to halt the growth of cancer cells. VHR is also upregulated in several cervix cancer cell lines as well as in carcinomas of the uterine cervix. Here we report the development of multidentate small-molecule inhibitors of VHR that inhibit its enzymatic activity at nanomolar concentrations and are selective for VHR over HePTP and MKP-1.</p><p>This novel chemical probe appears to interact with both the phosphate-binding pocket and several distinct hydrophobic regions within VHR’s active site, so it will serve as a useful tool in probing these interactions and elucidating the molecular mechanism of selectivity against this phosphatase and the functional consequences for cancer biology.</p><p>The probe decreased the proliferation of cervix cancer cells at low micromolar concentrations, while growth of primary normal keratinocytes was not affected. Thus this probe may also be a starting point to develop drugs for the treatment of cervical cancer.</p></div><div id="ml113.s4"><h2 id="_ml113_s4_">1. Scientific Rationale for Project</h2><div id="ml113.s5"><h3>Specific aims</h3><p>The overall goal is to develop selective and efficient VHR inhibitors for basic research on signal transduction processes and MAP kinase regulation. For the future, this work could also create proof-of concept evidence that VHR is a good drug target for the treatment of cervical cancer. Some of these inhibitors may turn out to be suitable for further development towards clinical use.</p></div><div id="ml113.s6"><h3>Background and Significance</h3><p>The Vaccinia H1-related (VHR) protein tyrosine phosphatase is a relatively small member of the
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subclass of dual-specificity phosphatases (<a class="bibr" href="#ml113.r1" rid="ml113.r1">1</a>) with only 185
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amino acids (mw 21 kDa) and with no apparent targeting domain or docking site.) (<a class="bibr" href="#ml113.r2" rid="ml113.r2">2</a>) Compared to the phospho-tyrosine (pTyr)- specific classical PTPs, the
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crystal structure of VHR revealed a much shallower active site, which allows VHR to act on both pTyr
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and phospho-threonine (pThr) in its substrates. (<a class="bibr" href="#ml113.r3" rid="ml113.r3">3</a>) VHR
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dephosphorylates and thereby inactivates extracellular signal-regulated kinases Erk1/2 and c-Jun
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N-terminal kinases Jnk1/2, but not p38. (<a class="bibr" href="#ml113.r4" rid="ml113.r4 ml113.r5 ml113.r6">4–6</a>) These mitogen-activated protein kinases (MAP kinases) mediate
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major signaling pathways triggered by extracellular growth factor, stress, or cytokines (<a class="bibr" href="#ml113.r7" rid="ml113.r7">7</a>) and regulate cellular processes such as differentiation,
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proliferation and apoptosis. (<a class="bibr" href="#ml113.r8" rid="ml113.r8">8</a>,<a class="bibr" href="#ml113.r9" rid="ml113.r9">9</a>) Unlike many MKPs, VHR expression is not induced in response to activation of MAP kinases (<a class="bibr" href="#ml113.r10" rid="ml113.r10">10</a>) but is instead regulated during cell cycle progression. (<a class="bibr" href="#ml113.r11" rid="ml113.r11">11</a>) The loss of VHR causes cell cycle arrest in HeLa carcinoma cells, suggesting that VHR inhibition may be a useful approach to halt the growth of cancer cells without the detrimental effects on normal cells. The assay provider recently reported that VHR is upregulated in several cervical cancer cell lines as well as in squamous intraepithelial lesions and squamous cell carcinomas of the uterine cervix. (<a class="bibr" href="#ml113.r12" rid="ml113.r12">12</a>)</p></div></div><div id="ml113.s7"><h2 id="_ml113_s7_">2. Project Description</h2><div id="ml113.s8"><h3>a. Original goal for probe characteristics</h3><p>The ideal probe would be a new scaffold of improved potency (< 2–3 µM) over current probes in the literature <i>and</i> improved selectivity towards other phosphatases (at least 2-fold over either MKP-1 or HePTP). However, as there are very few potent phosphatase inhibitors and even fewer selective ones, any improvement in either potency or selectivity would be useful. Additionally activity in a cell based assay for direct substrates is a desired characteristic; however, if none of the scaffolds obtained by catalog or by medicinal chemistry efforts have cell activity, the probes will still be useful as <i>in vitro</i> biochemical tools.</p><p>In the original CPDP, several compounds are disclosed as prior art, but none are more than potent than ~ 4 µM, reported as selective for VHR1 nor cell active without cellular toxicity and are reiterated below from H. Park <i>et al</i>. “Discovery of VHR Phosphatase Inhibitors with Micromolar Activity based on Structure-Based Virtual Screening” (2008) <i>J Med Chem</i>
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<b>3:</b>877 – 880 <i>(the authors do not specify the stereochemistry as E or Z for these olefins. However, they do mention that the vendor is Interbioscreen).</i></p><p>There was no cell activity reported for compounds <b>1 – 6</b> in <a class="figpopup" href="/books/NBK50693/figure/ml113.f1/?report=objectonly" target="object" rid-figpopup="figml113f1" rid-ob="figobml113f1">Figure 1</a>, <a class="figpopup" href="/books/NBK50693/table/ml113.t1/?report=objectonly" target="object" rid-figpopup="figml113t1" rid-ob="figobml113t1">Table 1</a> (but they may have not been tested in cell assays). Compounds <b>1</b> and <b>2</b> were purchased and provided to the assay provider for cell activity testing and reference.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml113f1" co-legend-rid="figlgndml113f1"><a href="/books/NBK50693/figure/ml113.f1/?report=objectonly" target="object" title="Figure 1" class="img_link icnblk_img figpopup" rid-figpopup="figml113f1" rid-ob="figobml113f1"><img class="small-thumb" src="/books/NBK50693/bin/ml113f1.gif" src-large="/books/NBK50693/bin/ml113f1.jpg" alt="Figure 1. Chemical structures of prior art VHR inhibitors from Park et al. 2008." /></a><div class="icnblk_cntnt" id="figlgndml113f1"><h4 id="ml113.f1"><a href="/books/NBK50693/figure/ml113.f1/?report=objectonly" target="object" rid-ob="figobml113f1">Figure 1</a></h4><p class="float-caption no_bottom_margin">Chemical structures of prior art VHR inhibitors from Park <i>et al.</i> 2008. </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml113t1"><a href="/books/NBK50693/table/ml113.t1/?report=objectonly" target="object" title="Table 1" class="img_link icnblk_img figpopup" rid-figpopup="figml113t1" rid-ob="figobml113t1"><img class="small-thumb" src="/books/NBK50693/table/ml113.t1/?report=thumb" src-large="/books/NBK50693/table/ml113.t1/?report=previmg" alt="Table 1. The inhibitory activities of compounds 1 -6 against VHR." /></a><div class="icnblk_cntnt"><h4 id="ml113.t1"><a href="/books/NBK50693/table/ml113.t1/?report=objectonly" target="object" rid-ob="figobml113t1">Table 1</a></h4><p class="float-caption no_bottom_margin">The inhibitory activities of compounds 1 -6 against VHR. <i>(adapted from Park et al. 2008)</i> </p></div></div><p>Additional VHR inhibitors (<a class="figpopup" href="/books/NBK50693/table/ml113.t2/?report=objectonly" target="object" rid-figpopup="figml113t2" rid-ob="figobml113t2">Table 2</a>, <a class="figpopup" href="/books/NBK50693/figure/ml113.f2/?report=objectonly" target="object" rid-figpopup="figml113f2" rid-ob="figobml113f2">Figure 2</a>) were reported by Zhi <i>et al</i>. “Identification of a Potent Inhibitor of Human Dual-Specific Phosphatase, VHR, from Computer-Aided and NMR-Based Screening to Cellular Effects” (2007) <i>ChemBioChem</i>
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<b>8:</b>2092–2099 GATPT is a stannous (tin containing compound and toxic) of no chemical interest or tractability. Has some reported cell activity, however it has been shown to be toxic.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml113t2"><a href="/books/NBK50693/table/ml113.t2/?report=objectonly" target="object" title="Table 2" class="img_link icnblk_img figpopup" rid-figpopup="figml113t2" rid-ob="figobml113t2"><img class="small-thumb" src="/books/NBK50693/table/ml113.t2/?report=thumb" src-large="/books/NBK50693/table/ml113.t2/?report=previmg" alt="Table 2. Inhibitory activities of compounds against VHRa." /></a><div class="icnblk_cntnt"><h4 id="ml113.t2"><a href="/books/NBK50693/table/ml113.t2/?report=objectonly" target="object" rid-ob="figobml113t2">Table 2</a></h4><p class="float-caption no_bottom_margin">Inhibitory activities of compounds against VHR<sup>a</sup>. (adapted from ZHI et al. 2007) </p></div></div><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml113f2" co-legend-rid="figlgndml113f2"><a href="/books/NBK50693/figure/ml113.f2/?report=objectonly" target="object" title="Figure 2" class="img_link icnblk_img figpopup" rid-figpopup="figml113f2" rid-ob="figobml113f2"><img class="small-thumb" src="/books/NBK50693/bin/ml113f2.gif" src-large="/books/NBK50693/bin/ml113f2.jpg" alt="Figure 2. Chemical structures of VHR inhibitors from Shi et al. 2007." /></a><div class="icnblk_cntnt" id="figlgndml113f2"><h4 id="ml113.f2"><a href="/books/NBK50693/figure/ml113.f2/?report=objectonly" target="object" rid-ob="figobml113f2">Figure 2</a></h4><p class="float-caption no_bottom_margin">Chemical structures of VHR inhibitors from Shi <i>et al.</i> 2007. </p></div></div><p>The following publications refer to these existing probes with PMIDs: 7556642, 11563920, 11755399, 17933004, and 18236492.</p></div><div id="ml113.s9"><h3>b. Information for each Assay Implemented and Screening Run</h3><div id="ml113.s10"><h4>i. PubChem Bioassay Name(s), AID(s), Assay-Type (Primary, DR, Counterscreen, Secondary)</h4><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml113t3"><a href="/books/NBK50693/table/ml113.t3/?report=objectonly" target="object" title="Table 3" class="img_link icnblk_img figpopup" rid-figpopup="figml113t3" rid-ob="figobml113t3"><img class="small-thumb" src="/books/NBK50693/table/ml113.t3/?report=thumb" src-large="/books/NBK50693/table/ml113.t3/?report=previmg" alt="Table 3. PubChem Assay Summaries for Probe project." /></a><div class="icnblk_cntnt"><h4 id="ml113.t3"><a href="/books/NBK50693/table/ml113.t3/?report=objectonly" target="object" rid-ob="figobml113t3">Table 3</a></h4><p class="float-caption no_bottom_margin">PubChem Assay Summaries for Probe project. </p></div></div></div><div id="ml113.s11"><h4>ii. Assay Rationale & Description</h4><p>The Vaccinia H1-related (VHR) PTP is a dual-specific Erk and Jnk phosphatase. This primary screen
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(<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1992" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1992</a>) is based on a biochemical assay that employs a colorimetric readout based on the
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enzyme’s ability to liberate phosphate from <i>para</i>-nitrophenyl phosphate
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(pNPP) and the reaction or the released phosphate with Biomol Green reagent. (<a class="bibr" href="#ml113.r13" rid="ml113.r13">13</a>) Following initial screening the hits are confirmed for activity using the same assay but from re-ordered stock solutions in duplicate single concentrations (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1992" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1992</a>), and then to determine the potency from full dose response curves (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2004" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2004</a>).</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml113t4"><a href="/books/NBK50693/table/ml113.t4/?report=objectonly" target="object" title="Table 4" class="img_link icnblk_img figpopup" rid-figpopup="figml113t4" rid-ob="figobml113t4"><img class="small-thumb" src="/books/NBK50693/table/ml113.t4/?report=thumb" src-large="/books/NBK50693/table/ml113.t4/?report=previmg" alt="Table 4. Reagents used for the HTS experiments." /></a><div class="icnblk_cntnt"><h4 id="ml113.t4"><a href="/books/NBK50693/table/ml113.t4/?report=objectonly" target="object" rid-ob="figobml113t4">Table 4</a></h4><p class="float-caption no_bottom_margin">Reagents used for the HTS experiments. </p></div></div><p><b>VHR materials</b></p><ol><li class="half_rhythm"><div>Recombinant VHR was provided by Prof. Lutz Tautz (Burnham Institute for Medical Research, San Diego, CA)</div></li><li class="half_rhythm"><div>Assay buffer: 0.1 M Bis-Tris pH 6.0 with 1 mM dithiothreitol (DTT)</div></li><li class="half_rhythm"><div>4 mM pNPP</div></li><li class="half_rhythm"><div>BIOMOL Green 2:1 addition to quench a 70 uL reaction volume</div></li></ol><p><b>VHR protocol</b></p><p>Each reaction contained 180 nM VHR, 4 mM pNPP, and 0.02 mg/mL compound in 0.1 M Bis-Tris pH 6.0 reaction buffer with 1 mM dithiothreitol (DTT) present. The final volume amounted to 70 μL and contained 1.4% DMSO. The reaction was initiated by addition of pNPP after a preincubation of the enzyme with compounds for 10 min at room temperature. After 15 min, the reaction was quenched by addition of 140 μL BIOMOL GREEN reagent, and the pNPP hydrolysis was determined by measuring the absorbance of the complexed free phosphate at 620 nm. The nonenzymatic hydrolysis of the substrate was corrected by measuring the negative control without addition of enzyme. Other controls included a positive control (no inhibitor added), a background control (no substrate added), and a control with 200 µM of the general PTP inhibitor sodium orthovanadate. To quantitate the inhibitory efficacy of the library compounds, we determined the ratio of inhibition in comparison to the positive control. Every compound with >60% inhibition was cherry-picked and rescreened to confirm it as a hit (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1992" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1992</a>) and confirmed for initial potency (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2004" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2004</a>).</p><div id="ml113.s16"><h5>Rationale for confirmatory, counter and selectivity assays</h5><div id="ml113.s17"><h5>VHR SAR assay</h5><p>A higher sensitivity fluorogenic assay was developed and performed to study the structure-activity relationship on analogs of the confirmed VHR hits reported in <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2004" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2004</a>. This VHR biochemical assay (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2074" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2074</a>) employs a fluorescent readout based on the enzyme’s ability to catalyze the hydrolysis of 6,8-difluoro-4-methylumbelliferyl phosphate (DiFMUP) in the presence of an inhibitor.</p></div><div id="ml113.s18"><h5>Counterassay (MKP-1)</h5><p>MAP kinase phosphatase 1 (MKP-1) is, <i>like VHR, a dual-specific</i> phosphatase and structurally closely related to VHR. MKP-1 also shares a physiological substrate with VHR, namely the extracellular signal-regulated kinases Erk1/2. Therefore, MKP-1 was chosen to assess the selectivity of the VHR1 inhibitors reported in <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2004" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2004</a>. This biochemical assay for MKP-1 (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2083" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2083</a>) employs the same fluorescent readout as the VHR SAR assay.</p></div><div id="ml113.s19"><h5>Selectivity Assay (HePTP)</h5><p>In contrast, the hematopoietic tyrosine phosphatase (HePTP) is a <i>classical</i> pTyr-specific phosphatase. HePTP shares a physiological substrate with VHR, namely the extracellular signal-regulated kinases Erk1/2, and therefore was chosen to assess the selectivity of the VHR1 inhibitors reported in <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2004" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2004</a>. This biochemical assay for HePTP (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2082" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2082</a>) also employs the same fluorescent readout as the VHR SAR assay. The commonality of the assay format and readout ensure comparability of potency values in these three assays.</p></div><div id="ml113.s20"><h5>General assay protocol</h5><p>The PTP-catalyzed hydrolysis of 6,8-difluoro-4-methylumbelliferyl phosphate (DiFMUP) in the presence of compound was assayed at 30°C in a 60 uL 96-well format reaction system in 150 mM Bis-Tris, pH 6.0, assay buffer having an ionic strength of 150 mM (adjusted with NaCl) and containing 1 mM DTT and 5%DMSO. At various concentrations of the compound, the initial rate at fixed DiFMUP concentration (equal to the corresponding Km value for each PTP) was determined using a FLx800 microplate reader (Bio-Tek Instruments, Inc.), an excitation wavelength of 360 nm, and measuring the emission of the fluorescent reaction product 6,8-difluoro-7-hydroxy-4-methylcoumarin (DiFMU) at 460 nm. The nonenzymatic hydrolysis of the substrate was corrected by measuring the control without addition of enzyme. The IC<sub>50</sub> value was determined by plotting the relative activity versus inhibitor concentration and fitting to <a href="#ml113.eq1">eq 1</a> using the software GraphPad Prism (GraphPad Software, Inc.).</p><div class="pmc_disp_formula whole_rhythm clearfix" id="ml113.eq1"><div class="inline_block pmc_inline_block pmc_va_middle pmc_hide_overflow eleven_col">
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<math id="ml113.m1" display="block"><semantics><mrow><msub><mrow><mi>V</mi></mrow><mi>i</mi></msub><mo>/</mo><msub><mrow><mi>V</mi></mrow><mn>0</mn></msub><mo>=</mo><msub><mrow><mi>I</mi><mi>C</mi></mrow><mrow><mn>50</mn></mrow></msub><mo>/</mo><mo stretchy="false">(</mo><msub><mrow><mi>I</mi><mi>C</mi></mrow><mrow><mn>50</mn></mrow></msub><mo>+</mo><mo stretchy="false">[</mo><mi>I</mi><mo stretchy="false">]</mo><mo stretchy="false">)</mo></mrow></semantics></math></div><div class="inline_block pmc_inline_block pmc_va_middle pmc_hide_overflow last bk_equ_label "><div><span class="nowrap">eq. 1</span></div></div></div><p>In this case, <i>V</i><i><sub>i</sub></i> is the reaction velocity when the inhibitor concentration is <i>[I]</i>, <i>V</i><i><sub>0</sub></i> is the reaction velocity with no inhibitor, and <i>IC</i><i><sub>50</sub></i><i>=K</i><i><sub>i</sub></i>
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<i>+ K</i><i><sub>i</sub></i><i>[S]/K</i><i><sub>m</sub></i>.</p></div></div></div><div id="ml113.s21"><h4>iii. Summary of Results</h4><p>We have completed the primary screen of 291,018 compounds from the MLSMR library (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1654" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1654</a>) using
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a colorimetric assay that measures the enzyme’s ability to liberate phosphate from
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<i>para</i>-nitrophenyl phosphate (PNPP) and detection of the released phosphate with
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Biomol Green reagent. However, at this juncture no VHR compounds of <2–3 µM potency with selectivity against other phosphatases (e.g. HePTP) were found. This probe report describes the results of a parallel screen of the 49,840 drug-like molecules of the DIVERSet library from ChemBridge, Inc. (San Diego, CA), at the concentration of 0.02 mg/mL in a 96-well format using an <i>in vitro</i> colorimetric phosphatase assay, in collaboration with the assay provider. The average Z′ for this assay was 0.85, the signal to background ratio was 3.8, the signal to noise ratio was 46.6 and the signal window was 34.7. We found that 221 compounds inhibited VHR’s enzymatic activity to >60% (average of n=2) compared to a no-inhibitor control. For further evaluation, a total of 56 compounds were picked that inhibited VHR>90% (average of n=2). Michaelis-Menten kinetic studies revealed 21 hits that inhibited the enzyme with K<sub>i</sub> values <20 µM (<a class="figpopup" href="/books/NBK50693/table/ml113.t5/?report=objectonly" target="object" rid-figpopup="figml113t5" rid-ob="figobml113t5">Table 5</a>). Clustering the 21 compounds by a Tanimoto distance (<a class="bibr" href="#ml113.r15" rid="ml113.r15">15</a>) of 0.5 resulted in 12 different clusters and singletons, respectively, indicating a quite diverse chemical space covered by these molecules. The most active hit, 2-((<i>Z</i>)-4-oxo-5-((<i>E</i>)-3-phenylallylidene)-2-thioxothiazolidin-3-yl)ethane-sulfonic acid, <a href="https://pubchem.ncbi.nlm.nih.gov/substance/17460170" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-17460170</a>
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<b>(1)</b>, inhibited VHR with a K<sub>i</sub> value of 0.81 µM. In a counter screen against the protein tyrosine phosphatase, HePTP, only <b>1</b> and 1,4-dimethoxyanthracene-9,10-dione, <a href="https://pubchem.ncbi.nlm.nih.gov/substance/17438068" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-17438068</a>
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<b>(8)</b>, and (1<i>E</i>,4<i>E</i>)-1-[5-(3,4-dichlorophenyl)furan-2-yl]-5-(furan-2-yl)penta-1,4-dien-3-one, <a href="https://pubchem.ncbi.nlm.nih.gov/substance/17461020" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-17461020</a>
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<b>(18)</b> were found to be selective for VHR (<a class="figpopup" href="/books/NBK50693/figure/ml113.f3/?report=objectonly" target="object" rid-figpopup="figml113f3" rid-ob="figobml113f3">Figure 3</a>).</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml113t5"><a href="/books/NBK50693/table/ml113.t5/?report=objectonly" target="object" title="Table 5" class="img_link icnblk_img figpopup" rid-figpopup="figml113t5" rid-ob="figobml113t5"><img class="small-thumb" src="/books/NBK50693/table/ml113.t5/?report=thumb" src-large="/books/NBK50693/table/ml113.t5/?report=previmg" alt="Table 5. Most Potent VHR Screening Hits." /></a><div class="icnblk_cntnt"><h4 id="ml113.t5"><a href="/books/NBK50693/table/ml113.t5/?report=objectonly" target="object" rid-ob="figobml113t5">Table 5</a></h4><p class="float-caption no_bottom_margin">Most Potent VHR Screening Hits. </p></div></div><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml113f3" co-legend-rid="figlgndml113f3"><a href="/books/NBK50693/figure/ml113.f3/?report=objectonly" target="object" title="Figure 3" class="img_link icnblk_img figpopup" rid-figpopup="figml113f3" rid-ob="figobml113f3"><img class="small-thumb" src="/books/NBK50693/bin/ml113f3.gif" src-large="/books/NBK50693/bin/ml113f3.jpg" alt="Figure 3. Profiling of the 21 most active VHR screening hits at 20 µM against VHR (AID-2074) & HePTP (AID-2082)." /></a><div class="icnblk_cntnt" id="figlgndml113f3"><h4 id="ml113.f3"><a href="/books/NBK50693/figure/ml113.f3/?report=objectonly" target="object" rid-ob="figobml113f3">Figure 3</a></h4><p class="float-caption no_bottom_margin">Profiling of the 21 most active VHR screening hits at 20 µM against VHR (AID-2074) &
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HePTP (AID-2082). Asterisks indicate compounds 1, 8, and 18 (Table 5), which appeared to be selectively inhibiting VHR without HePTP inhibition </p></div></div><p>Of these three compounds, only <a href="https://pubchem.ncbi.nlm.nih.gov/substance/17460170" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-17460170</a>
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<b>(1)</b>, showed a clear competitive inhibition pattern as shown in the Lineweaver-Burk plot in <a class="figpopup" href="/books/NBK50693/figure/ml113.f4/?report=objectonly" target="object" rid-figpopup="figml113f4" rid-ob="figobml113f4">Figure 4A</a>.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml113f4" co-legend-rid="figlgndml113f4"><a href="/books/NBK50693/figure/ml113.f4/?report=objectonly" target="object" title="Figure 4" class="img_link icnblk_img figpopup" rid-figpopup="figml113f4" rid-ob="figobml113f4"><img class="small-thumb" src="/books/NBK50693/bin/ml113f4.gif" src-large="/books/NBK50693/bin/ml113f4.jpg" alt="Figure 4. Characterization of SID-17460170 (1)." /></a><div class="icnblk_cntnt" id="figlgndml113f4"><h4 id="ml113.f4"><a href="/books/NBK50693/figure/ml113.f4/?report=objectonly" target="object" rid-ob="figobml113f4">Figure 4</a></h4><p class="float-caption no_bottom_margin">Characterization of SID-17460170
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<i>(1).</i> (A) Michaelis-Menten kinetic
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measurements, Lineweaver-Burk plots for SID-17460170
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<i>(1)</i> with VHR. (B) FlexX docking of SID-17460170
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<i>(1)</i> into the active site of VHR crystal structure (PDB code 1J4X). The color code of <a href="/books/NBK50693/figure/ml113.f4/?report=objectonly" target="object" rid-ob="figobml113f4">(more...)</a></p></div></div></div></div><div id="ml113.s22"><h3>c. Probe Optimization</h3><div id="ml113.s23"><h4>i. Description of SAR & chemistry strategy (including structure and data) that led to the probe</h4><div id="ml113.s24"><h5><i>In Silico</i> Docking</h5><p>To study the molecular basis for inhibition of VHR, we first used <i>in silico</i>
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docking to dock <a href="https://pubchem.ncbi.nlm.nih.gov/substance/17460170" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-17460170</a>
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<b>(1)</b> and <a href="https://pubchem.ncbi.nlm.nih.gov/substance/17438068" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-17438068</a>
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<b>(8)</b> into the active site
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of the VHR crystal structure (PDB code1J4X, ref <a class="bibr" href="#ml113.r16" rid="ml113.r16">16</a>).
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Compound <a href="https://pubchem.ncbi.nlm.nih.gov/substance/17438068" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-17438068</a>
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<b>(8)</b> failed to dock into the catalytic pocket, further supporting an inhibition mechanism other than competitive. Because quinones like <a href="https://pubchem.ncbi.nlm.nih.gov/substance/17438068" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-17438068</a>
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<b>(8)</b> are known to deactivate PTPs by oxidizing the catalytic cysteine residue, (<a class="bibr" href="#ml113.r7" rid="ml113.r7">7</a>) so we discarded <a href="https://pubchem.ncbi.nlm.nih.gov/substance/17438068" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-17438068</a>
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<b>(8)</b> from further investigation. As for compound <a href="https://pubchem.ncbi.nlm.nih.gov/substance/17460170" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-17460170</a>
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<b>(1)</b>, the docking suggested that the sulfonic acid moiety functions as a phosphate mimic and binds into the catalytic pocket, forming a network of hydrogen bond interactions with the phosphate binding loop, also called P-loop (<a class="figpopup" href="/books/NBK50693/figure/ml113.f2/?report=objectonly" target="object" rid-figpopup="figml113f2" rid-ob="figobml113f2">Figure 2B</a>). In support of this, similar compounds lacking the sulfonic acid moiety did not inhibit VHR. Furthermore, the docking suggested that the oxo-thioxothiazolidine ring interacts with the rim of the catalytic pocket, whereas the diene linker and the phenyl ring make van der Waals interactions with a hydrophobic region, mainly formed by Leu25 and Tyr128 (<a class="figpopup" href="/books/NBK50693/figure/ml113.f2/?report=objectonly" target="object" rid-figpopup="figml113f2" rid-ob="figobml113f2">Figure 2B</a>, above).</p></div><div id="ml113.s25"><h5>SAR Analysis and Analogs of Lead Compound 1</h5><p>By further analyzing the lipophilic potential of VHR’s active site surface area, we found
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a total of three distinct hydrophobic regions surrounding the catalytic pocket (<a class="figpopup" href="/books/NBK50693/figure/ml113.f2/?report=objectonly" target="object" rid-figpopup="figml113f2" rid-ob="figobml113f2">Figure 2B</a>). Compared to active site properties of solved PTP structures and
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homology models, (<a class="bibr" href="#ml113.r17" rid="ml113.r17">17</a>) this feature seems to be rather unique to VHR and, therefore, could be exploited for designing selective inhibitors. The exposed hydrophobic patches are formed by Leu25/Tyr128 and Leu16/Tyr23, which make up large portions of the substrate binding site, (<a class="bibr" href="#ml113.r10" rid="ml113.r10">10</a>) as well as by Phe68/Met69, which is part of a loop opposite of the catalytic pocket (<a class="figpopup" href="/books/NBK50693/figure/ml113.f2/?report=objectonly" target="object" rid-figpopup="figml113f2" rid-ob="figobml113f2">Figure 2B</a>). In an attempt to find analogs of 1 that could target more than one of these hydrophobic regions, we kept the oxo-thioxothiazolidinyl-ethanesulfonic acid moiety as hydrophilic pharmacophore, and subjected it to a substructure search among commercially available compounds. The pharmacophore model and limited R-group search is summarized below:</p><div id="ml113.fu2" class="figure"><div class="graphic"><img src="/books/NBK50693/bin/ml113fu23.jpg" alt="Image ml113fu23" /></div></div><p>Six structures were identified that fulfilled the requirement of having additional multiple hydrophobic entities to interact with multiple hydrophobic regions in VHR’s active site. All compounds contained a 1-phenyl-substituted pyrazole ring, which at its 3-position linked to another, more variable entity (see <a class="figpopup" href="/books/NBK50693/table/ml113.t6/?report=objectonly" target="object" rid-figpopup="figml113t6" rid-ob="figobml113t6">Table 6</a>). We obtained all six analogs and subjected them to direct measurements of VHR inhibition. Indeed, compounds CID-6161281, -6274486, -5932584, -5998084, and -6166563 (<b>SA1-5)</b> showed excellent IC<sub>50</sub> values of 18, 71, 74, 78, and 268 nM, respectively (<a class="figpopup" href="/books/NBK50693/table/ml113.t6/?report=objectonly" target="object" rid-figpopup="figml113t6" rid-ob="figobml113t6">Table 6</a>). An aromatic group in position ‘R’, such as the benzoxy group in compounds CID-6161281, -6274486, -5932584, and -5998084 (<b>SA1-4)</b>, seemed to be very well accommodated by the protein, whereas sterically more demanding structures, such as the piperidinesulfonyl group in CID-6166563 (<b>SA5)</b> were less favorable. On the other hand, groups such as methyl in CID-6001181 (<b>SA6)</b> seemed to be too small to provide additional binding energy through van der Waals interactions. Interestingly, compounds CID-6161281, -6274486, -5932584, and -5998084 (<b>SA1-4)</b> only differ in their substituents at the benzoxy group. Chlorine in the <i>para</i> position was most favorable CID-6161281 (<b>SA1</b>), whereas substituents in the <i>ortho</i>-position, such as chlorine CID-6274486 (<b>SA2</b>) or fluorine CID-5932584 (<b>SA3</b>), had no effect on inhibitory activity against VHR <i>in vitro</i>. Testing the five best inhibitors CID-6161281, -6274486, -5932584, -5998084, and -6166563 (<b>SA1-5</b>) against a panel of related PTPs demonstrated that they were at least 1 order of magnitude less potent for MKP-1 and HePTP (<a class="figpopup" href="/books/NBK50693/table/ml113.t6/?report=objectonly" target="object" rid-figpopup="figml113t6" rid-ob="figobml113t6">Table 6</a>). MKP-1 and HePTP share the same physiological substrate with VHR, namely, the MAP kinase Erk, and MKP-1 is structurally closely related to VHR.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml113t6"><a href="/books/NBK50693/table/ml113.t6/?report=objectonly" target="object" title="Table 6" class="img_link icnblk_img figpopup" rid-figpopup="figml113t6" rid-ob="figobml113t6"><img class="small-thumb" src="/books/NBK50693/table/ml113.t6/?report=thumb" src-large="/books/NBK50693/table/ml113.t6/?report=previmg" alt="Table 6. In vitro potency and Selectivity of 1-phenylpyrazole VHR inhibitor analogs." /></a><div class="icnblk_cntnt"><h4 id="ml113.t6"><a href="/books/NBK50693/table/ml113.t6/?report=objectonly" target="object" rid-ob="figobml113t6">Table 6</a></h4><p class="float-caption no_bottom_margin"><i>In vitro</i> potency and Selectivity of 1-phenylpyrazole VHR inhibitor analogs. </p></div></div></div></div></div></div><div id="ml113.s26"><h2 id="_ml113_s26_">3. Probe</h2><div id="ml113.s27"><h3>a. Chemical name of probe compound</h3><p><b>IUPAC</b>: 2-[(5Z)-5-[[3-[4-[(4-chlorophenyl)methoxy]phenyl]-1-phenylpyrazol-4-yl]methylidene]-4-oxo-2-sulfanylidene-1,3-thiazolidin-3-yl]ethanesulfonic acid [<b><a href="/pcsubstance/?term=ML113[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML113</a>]</b></p></div><div id="ml113.s28"><h3>b. Probe chemical structure including stereochemistry</h3><div id="ml113.fu3" class="figure"><div class="graphic"><img src="/books/NBK50693/bin/ml113fu29.jpg" alt="Image ml113fu29" /></div></div></div><div id="ml113.s29"><h3>c. Structural verification information of probe SID</h3><p>Probe SID number is <a href="https://pubchem.ncbi.nlm.nih.gov/substance/85256223" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-85256223</a> Purity: >95% (HPLC-MS)</p><div id="ml113.fu4" class="figure"><div class="graphic"><img src="/books/NBK50693/bin/ml113fu30.jpg" alt="Image ml113fu30" /></div></div><div id="ml113.fu5" class="figure"><div class="graphic"><img src="/books/NBK50693/bin/ml113fu31.jpg" alt="Image ml113fu31" /></div></div></div><div id="ml113.s30"><h3>d. PubChem CID (corresponding to the SID)</h3><p>PubChem CID is 6161281 (corresponding to <a href="https://pubchem.ncbi.nlm.nih.gov/substance/85256223" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-85256223</a>)</p></div><div id="ml113.s31"><h3>e. Availability from a vendor</h3><p>This probe molecule is available from Princeton BioMolecular Research, Inc. (Monmouth Jct, NJ) with a catalog number of OSSK_022127 (<i><a href="http://www.princetonbio.com" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.princetonbio.com</a>)</i></p></div><div id="ml113.s32"><h3>f. MLS#'s of probe molecule and five related samples that were submitted to the SMR collection</h3><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml113t7"><a href="/books/NBK50693/table/ml113.t7/?report=objectonly" target="object" title="Table 7" class="img_link icnblk_img figpopup" rid-figpopup="figml113t7" rid-ob="figobml113t7"><img class="small-thumb" src="/books/NBK50693/table/ml113.t7/?report=thumb" src-large="/books/NBK50693/table/ml113.t7/?report=previmg" alt="Table 7. Submission of Probe and 5 analogs to the MLSMR." /></a><div class="icnblk_cntnt"><h4 id="ml113.t7"><a href="/books/NBK50693/table/ml113.t7/?report=objectonly" target="object" rid-ob="figobml113t7">Table 7</a></h4><p class="float-caption no_bottom_margin">Submission of Probe and 5 analogs to the MLSMR. </p></div></div></div><div id="ml113.s33"><h3>g. Mode of action for biological activity of probe</h3><p>The resulting lead compound <a href="https://pubchem.ncbi.nlm.nih.gov/substance/17460170" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-17460170</a>
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<b>(1)</b> competitively inhibited VHR with a
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K<sub>i</sub> value of 0.81 µM and exhibited a promising degree of selectivity for VHR among other
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PTPs. <i>In silico</i> docking of <a href="https://pubchem.ncbi.nlm.nih.gov/substance/17460170" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-17460170</a>
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<b>(1)</b> into the active site of VHR
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and SAR analysis suggested a binding mode, in which the sulfonic acid moiety of <a href="https://pubchem.ncbi.nlm.nih.gov/substance/17460170" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-17460170</a>
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<b>(1)</b> binds through a network of hydrogen bond interactions into the phosphate binding pocket, whereas the thiazolidine heterocycle interacts with the rim of the pocket and the phenyl-allyl moiety makes van der Waals interactions with side chains of hydrophobic amino acids that flank the active site. Besides highly improved potency against VHR with IC<sub>50</sub> values as low as 18 nM, these multidentate inhibitors were at least 1 order of magnitude less potent for any other PTP tested, including HePTP and MKP-1, which share the same physiological substrate with VHR. This result provides a good example for a general applicable concept, in which targeting unique surface features outside of the catalytic pocket can generate selective small-molecule inhibitors for individual members of the PTP family. (<a class="bibr" href="#ml113.r18" rid="ml113.r18">18</a>)</p><p>The assay provider, Dr. Tautz found that VHR inhibitors are able to pass cell membrane barriers
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and target VHR in cultured cells. (<a class="bibr" href="#ml113.r18" rid="ml113.r18">18</a>) In particular, he tested the compounds in cervical cancer cells, which were shown earlier to express higher levels of endogenous VHR compared to noncancerous cells of the cervix. Indeed, incubation of the cancer cell line HeLa and CaSki with the inhibitors at 20 µM induced a very significant inhibition of cell proliferation after an incubation period as short as 24 h.</p><p>It is interesting to note that CID-5932584 (<b>SA3</b>) was more effective in inhibiting proliferation than CID-6161281 (<b>SA1</b>), although its IC<sub>50</sub> value is four times higher <i>in vitro</i>. CID-5932584 (<b>SA3</b>) also exhibited greater antiproliferative effects than CID-6274486 (<b>SA2</b>) and CID-5998084 (<b>SA4)</b>, both of which share similar IC<sub>50</sub> values with CID-5932584 (<b>SA3</b>) <i>in vitro</i>.</p><p>These results suggest a beneficial role for the fluorine substituent (which is only present in CID-5932584 (<b>SA3</b>), maybe by facilitating better membrane permeability. The latter could be a limiting factor for these compounds, considering the substantially higher concentration that is needed to see clear effects in cells vs. inhibition of recombinant protein. Nonetheless, the fact that these inhibitors are not toxic to cells with low levels of endogenous VHR, such as primary normal keratinocytes, these compounds may well be a starting point for development of drugs for the treatment of cervical cancer and perhaps other cancers. Indeed, our results provide first evidence that pharmacological inhibition of VHR could be beneficial in treating such diseases. However, additional studies will be necessary to get better insights into the role of VHR phosphatase in cell cycle regulation and cancer and to test the activity of these compounds <i>in vivo</i> using mouse models.</p><div id="ml113.f5" class="figure bk_fig"><div class="graphic"><img src="/books/NBK50693/bin/ml113f5.jpg" alt="Figure 4. Effects of VHR inhibitors on proliferation and survival of cervix cancer cells." /></div><h3><span class="label">Figure 4</span><span class="title">Effects of VHR inhibitors on proliferation and survival of cervix cancer cells</span></h3><div class="caption"><p>(A)
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Cell numbers of HeLa cervix carcinoma cells and normal keratinocytes (NK) after 24 h of treatment with 20 µM inhibitors, given as percentage of the DMSO control. (B,C) [3H]-Thymidine incorporation assay with 20 µM inhibitors or vehicle (DMSO) in HeLa (B) or Caski (C) cervix cancer carcinoma cells. (D) Survival/death of HeLa and CasKi cells in presence of 20 µM inhibitors or DMSO after 24 h, evaluated by Annexin V FITC/PI flow cytometry assay (FACS Vantage, BD). Percentage of live cells (Annexin V negative and PI negative cells on flow cytometry dot plots) is given. All data are reported as mean ± SD from three independent experiments. (see ref. <a class="bibr" href="#ml113.r18" rid="ml113.r18">18</a>)</p></div></div></div><div id="ml113.s34"><h3>h. Detailed synthetic pathway for making probe</h3><p>Compound is obtained commercially, but BCCG did prepare a synthetic route.</p></div><div id="ml113.s35"><h3>i. Summary of probe properties (solubility, absorbance/fluorescence, reactivity, toxicity, etc.)</h3><p>This probe has demonstrated low micromolar potency for VHR and selectivity against HePTP and MKP-1. In PubChem this compounds has been tested in only the SAR assays associated with the VHR project.</p><p>While the probe compound CID6161281 [<b><a href="/pcsubstance/?term=ML113[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML113</a>]</b> (MLS-0425632) contains a sulfonic acid that is expected to be fully negatively charged, however, it is also a very hydrophobic molecule. Consistent with these characteristics, it exhibited low solubility and permeability at all pHs tested (<a class="figpopup" href="/books/NBK50693/table/ml113.t8/?report=objectonly" target="object" rid-figpopup="figml113t8" rid-ob="figobml113t8">Table 8</a>). It exhibits high plasma protein binding (both human and mouse). However, it has good stability in both human and mouse plasma. But, it has some instability in the presence of both human and mouse microsomes (determined by the exploratory pharmacology group). The probe compound has a LD<sub>50</sub> >50µM towards Fa2N-4 immortalized human hepatocytes.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml113t8"><a href="/books/NBK50693/table/ml113.t8/?report=objectonly" target="object" title="Table 8" class="img_link icnblk_img figpopup" rid-figpopup="figml113t8" rid-ob="figobml113t8"><img class="small-thumb" src="/books/NBK50693/table/ml113.t8/?report=thumb" src-large="/books/NBK50693/table/ml113.t8/?report=previmg" alt="Table 8. Summary of in vitro ADMET/PK Properties of HePTP Inhibitor Probe." /></a><div class="icnblk_cntnt"><h4 id="ml113.t8"><a href="/books/NBK50693/table/ml113.t8/?report=objectonly" target="object" rid-ob="figobml113t8">Table 8</a></h4><p class="float-caption no_bottom_margin">Summary of <i>in vitro</i> ADMET/PK Properties of HePTP Inhibitor Probe. </p></div></div></div><div id="ml113.s36"><h3>j. Probe properties</h3><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml113t9"><a href="/books/NBK50693/table/ml113.t9/?report=objectonly" target="object" title="Table 9" class="img_link icnblk_img figpopup" rid-figpopup="figml113t9" rid-ob="figobml113t9"><img class="small-thumb" src="/books/NBK50693/table/ml113.t9/?report=thumb" src-large="/books/NBK50693/table/ml113.t9/?report=previmg" alt="Table 9. Properties computed from Structure." /></a><div class="icnblk_cntnt"><h4 id="ml113.t9"><a href="/books/NBK50693/table/ml113.t9/?report=objectonly" target="object" rid-ob="figobml113t9">Table 9</a></h4><p class="float-caption no_bottom_margin">Properties computed from Structure. </p></div></div></div></div><div id="ml113.s37"><h2 id="_ml113_s37_">4. Appendices</h2><div id="ml113.s38"><h3>a. Comparative data on (1) probe, (2) similar compound structures (establishing SAR) and (3) prior probes</h3><p>Already summarized above in <a class="figpopup" href="/books/NBK50693/table/ml113.t1/?report=objectonly" target="object" rid-figpopup="figml113t1" rid-ob="figobml113t1">Tables 1</a>, <a class="figpopup" href="/books/NBK50693/table/ml113.t2/?report=objectonly" target="object" rid-figpopup="figml113t2" rid-ob="figobml113t2">2</a>, <a class="figpopup" href="/books/NBK50693/table/ml113.t5/?report=objectonly" target="object" rid-figpopup="figml113t5" rid-ob="figobml113t5">5</a> and <a class="figpopup" href="/books/NBK50693/table/ml113.t6/?report=objectonly" target="object" rid-figpopup="figml113t6" rid-ob="figobml113t6">6</a></p></div><div id="ml113.s39"><h3>b. Comparative data showing probe specificity for target</h3><p>Already summarized above in <a class="figpopup" href="/books/NBK50693/table/ml113.t6/?report=objectonly" target="object" rid-figpopup="figml113t6" rid-ob="figobml113t6">Table 6</a></p></div></div><div id="ml113.s40"><h2 id="_ml113_s40_">5. Bibliography</h2><dl class="temp-labeled-list"><dl class="bkr_refwrap"><dt>1.</dt><dd><div class="bk_ref" id="ml113.r1">Alonso A, Sasin J, Bottini N, Friedberg I, Friedberg I, Osterman A, Godzik A, Hunter T, Dixon J, Mustelin T. Protein tyrosine phosphatases in the human genome. <span><span class="ref-journal">Cell. </span>2004;<span class="ref-vol">117</span>:699–711.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15186772" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15186772</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>2.</dt><dd><div class="bk_ref" id="ml113.r2">Ishibashi T, Bottaro DP, Chan A, Miki T, Aaronson SA. Expression cloning of a human dual-specificity phosphatase. <span><span class="ref-journal">Proc Natl Acad Sci USA. </span>1992;<span class="ref-vol">89</span>:12170–12174.</span> [<a href="/pmc/articles/PMC50720/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC50720</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/1281549" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 1281549</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>3.</dt><dd><div class="bk_ref" id="ml113.r3">Yuvaniyama J, Denu JM, Dixon JE, Saper MA. Crystal structure of the dual specificity protein phosphatase VHR. <span><span class="ref-journal">Science. </span>1996;<span class="ref-vol">272</span>:1328–1331.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/8650541" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8650541</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>4.</dt><dd><div class="bk_ref" id="ml113.r4">Alonso A, Saxena M, Williams S, Mustelin T. Inhibitory role for dual specificity phosphatase VHR in T cell antigen receptor and CD28-induced Erk and Jnk activation. <span><span class="ref-journal">J Biol Chem. </span>2001;<span class="ref-vol">276</span>:4766–4771.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11085983" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11085983</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>5.</dt><dd><div class="bk_ref" id="ml113.r5">Todd JL, Rigas JD, Rafty LA, Denu JM. Dual-specificity protein tyrosine phosphatase VHR down-regulates c-Jun N-terminal kinase (JNK). <span><span class="ref-journal">Oncogene. </span>2002;<span class="ref-vol">21</span>:2573–2583.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11971192" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11971192</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>6.</dt><dd><div class="bk_ref" id="ml113.r6">Todd JL, Tanner KG, Denu JM. Extracellular regulated kinases (ERK) 1 and ERK2 are authentic substrates for the dual specificity protein-tyrosine phosphatase VHR. A novel role in down-regulating the ERK pathway. <span><span class="ref-journal">J Biol Chem. </span>1999;<span class="ref-vol">274</span>:13271–13280.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/10224087" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10224087</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>7.</dt><dd><div class="bk_ref" id="ml113.r7">Waskiewicz AJ, Cooper JA. Mitogen and stress response pathways: MAP kinase cascades and phosphatase regulation in mammals and yeast. <span><span class="ref-journal">Curr Opin Cell Biol. </span>1995;<span class="ref-vol">7</span>:798–805.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/8608010" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8608010</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>8.</dt><dd><div class="bk_ref" id="ml113.r8">Robinson MJ, Cobb MH. Mitogen-activated protein kinase pathways. <span><span class="ref-journal">Curr Opin Cell Biol. </span>1997;<span class="ref-vol">9</span>:180–186.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9069255" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9069255</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>9.</dt><dd><div class="bk_ref" id="ml113.r9">Ip YT, Davis RJ. Signal transduction by the c-Jun N-terminal kinase (JNK); from inflammation to development. <span><span class="ref-journal">Curr Opin Cell Biol. </span>1998;<span class="ref-vol">10</span>:205–219.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9561845" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9561845</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>10.</dt><dd><div class="bk_ref" id="ml113.r10">Alonso A, Saxena M, Williams S, Mustelin T. Inhibitory role for dual specificity phosphatase VHR in T cell antigen receptor and CD28-induced Erk and Jnk activation. <span><span class="ref-journal">J Biol Chem. </span>2001;<span class="ref-vol">276</span>:4766–4771.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11085983" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11085983</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>11.</dt><dd><div class="bk_ref" id="ml113.r11">Rahmouni S, Cerignoli F, Alonso A, Tsutji T, Henkens R, Zhu C, Louis-dit-Sully C, Moutschen M, Jiang W, Mustelin T. Loss of the VHR dual-specific phosphatase causes cell-cycle arrest and senescence. <span><span class="ref-journal">Nat Cell Biol. </span>2006;<span class="ref-vol">8</span>:524–531.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16604064" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16604064</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>12.</dt><dd><div class="bk_ref" id="ml113.r12">Henkens R, Delvenne P, Arafa M, Moutschen M, Zeddou M, Tautz L, Boniver J, Mustelin T, Rahmouni S. Cervix carcinoma is associated with an up-regulation and nuclear localization of the dual-specificity protein phosphatase VHR. <span><span class="ref-journal">BMC Cancer. </span>2008;<span class="ref-vol">8</span>:147.</span> [<a href="/pmc/articles/PMC2413255/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2413255</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18505570" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18505570</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>13.</dt><dd><div class="bk_ref" id="ml113.r13">Tautz L, Mustelin T. Strategies for developing protein tyrosine phosphatase inhibitors. <span><span class="ref-journal">Methods. </span>2007;<span class="ref-vol">42</span>:250–260.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17532512" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17532512</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>14.</dt><dd><div class="bk_ref" id="ml113.r14">Tautz L, Bruckner S, Sareth S, Alonso A, Bogetz J, Bottini N, Pellecchia M, Mustelin T. Inhibition of Yersinia tyrosine phosphatase by furanyl salicylate compounds. <span><span class="ref-journal">J Biol Chem. </span>2005;<span class="ref-vol">280</span>:9400–8.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15615724" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15615724</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>15.</dt><dd><div class="bk_ref" id="ml113.r15">Willett P. Similarity-based virtual screening using 2D fingerprints. <span><span class="ref-journal">Drug Discovery Today. </span>2006;<span class="ref-vol">11</span>:1046–1053.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17129822" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17129822</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>16.</dt><dd><div class="bk_ref" id="ml113.r16">Schumacher MA, Todd JL, Rice AE, Tanner KG, Denu JM. Structural basis for the recognition of a bisphosphorylated MAP kinase peptide by human VHR protein Phosphatase. <span><span class="ref-journal">Biochemistry. </span>2002;<span class="ref-vol">41</span>:3009–3017.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11863439" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11863439</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>17.</dt><dd><div class="bk_ref" id="ml113.r17">Barr AJ, Ugochukwu E, Lee WH, King ON, Filippakopoulos P, Alfano I, Savitsky P, Burgess-Brown NA, Muller S, Knapp S. Large-scale structural analysis of the classical human protein tyrosine phosphatome. <span><span class="ref-journal">Cell. </span>2009;<span class="ref-vol">136</span>:352–363.</span> [<a href="/pmc/articles/PMC2638020/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2638020</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19167335" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19167335</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>18.</dt><dd><div class="bk_ref" id="ml113.r18">Wu S, Vossius S, Rahmouni Miletic AV, Vang T, Vazquez-Rodriguez J, Cerignoli F, Arimura Y, Williams S, Hayes T, Moutschen M, Vasile S, Pellecchia M, Mustelin T, Tautz L. Multidentate Small-Molecule Inhibitors of Vaccinia. H1-Related (VHR) Phosphatase Decrease Proliferation of Cervix Cancer Cells. <span><span class="ref-journal">J Med Chem. </span>2009 Nov 12;<span class="ref-vol">52</span>(21):6716–23.</span> [PubMed - in process] [<a href="/pmc/articles/PMC2790023/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2790023</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19888758" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19888758</span></a>]</div></dd></dl></dl></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK50693_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><p class="contrib-group"><h4>Authors</h4><span itemprop="author">Lutz Tautz</span>, <span itemprop="author">Tomas Mustelin</span>, <span itemprop="author">Shuangding Wu</span>, <span itemprop="author">Sofie Vossius</span>, <span itemprop="author">Souad Rahmouni</span>, <span itemprop="author">Stefan Vasile</span>, <span itemprop="author">Eduard Sergienko</span>, <span itemprop="author">Derek Stonich</span>, <span itemprop="author">Hongbin Yuan</span>, <span itemprop="author">Ying Su</span>, <span itemprop="author">Russell Dahl</span>, <span itemprop="author">Yalda Mostofi</span>, and <span itemprop="author">Thomas DY Chung</span>.</p><h3>Publication History</h3><p class="small">Received: <span itemprop="datePublished">October 31, 2009</span>; Last Update: <span itemprop="dateModified">October 4, 2010</span>.</p><h3>Copyright</h3><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright Notice</a></div></div><h3>Publisher</h3><p>National Center for Biotechnology Information (US), Bethesda (MD)</p><h3>NLM Citation</h3><p>Tautz L, Mustelin T, Wu S, et al. Small-Molecule Inhibitors of Vaccinia-H1-Related Phosphatase VHR. 2009 Oct 31 [Updated 2010 Oct 4]. In: Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010-. <span class="bk_cite_avail"></span></p></div><div class="small-screen-prev"><a href="/books/n/mlprobe/ml114/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M75,30 c-80,60 -80,0 0,60 c-30,-60 -30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Prev</text></svg></a></div><div class="small-screen-next"><a href="/books/n/mlprobe/ml112/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M25,30c80,60 80,0 0,60 c30,-60 30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Next</text></svg></a></div></article><article data-type="fig" id="figobml113fu1"><div id="ml113.fu1" class="figure"><div class="graphic"><img data-src="/books/NBK50693/bin/ml113fu1.jpg" alt="Image ml113fu1" /></div></div></article><article data-type="table-wrap" id="figobml113tu1"><div id="ml113.tu1" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK50693/table/ml113.tu1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml113.tu1_lrgtbl__"><table><thead><tr><th id="hd_h_ml113.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CID/ML</th><th id="hd_h_ml113.tu1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Target Name</th><th id="hd_h_ml113.tu1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">IC50/EC50 (nM) [SID, AID]</th><th id="hd_h_ml113.tu1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Anti-target Name(s)</th><th id="hd_h_ml113.tu1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">IC50/EC50 (µM) [SID, AID]</th><th id="hd_h_ml113.tu1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Selectivity</th><th id="hd_h_ml113.tu1_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Secondary Assay(s) Name: IC50/EC50 (nM) [SID, AID]</th></tr></thead><tbody><tr><td headers="hd_h_ml113.tu1_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:top;">CID 6161281<br /><br /><a href="/pcsubstance/?term=ML113[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML113</a></td><td headers="hd_h_ml113.tu1_1_1_1_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:top;">VHR</td><td headers="hd_h_ml113.tu1_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:top;">IC50 18 (nM)<br /><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85256223" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-85256223</a><br /><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2074" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2074</a></td><td headers="hd_h_ml113.tu1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">MKP-1 in-class dual specific PTP</td><td headers="hd_h_ml113.tu1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">IC50 0.46 (µM)<br /><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85256223" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-85256223</a><br /><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2083" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2083</a></td><td headers="hd_h_ml113.tu1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">25.6X</td><td headers="hd_h_ml113.tu1_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">N/A</td></tr><tr><td headers="hd_h_ml113.tu1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">HePTP out-of- class classical PTP</td><td headers="hd_h_ml113.tu1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">IC50 0.62 (µM)<br /><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85256223" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-85256223</a><br /><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2082" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2082</a></td><td headers="hd_h_ml113.tu1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">34.4X</td><td headers="hd_h_ml113.tu1_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td></tr></tbody></table></div></div></article><article data-type="fig" id="figobml113f1"><div id="ml113.f1" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK50693/bin/ml113f1.jpg" alt="Figure 1. Chemical structures of prior art VHR inhibitors from Park et al. 2008." /></div><h3><span class="label">Figure 1</span><span class="title">Chemical structures of prior art VHR inhibitors from Park <i>et al.</i> 2008</span></h3></div></article><article data-type="table-wrap" id="figobml113t1"><div id="ml113.t1" class="table"><h3><span class="label">Table 1</span><span class="title">The inhibitory activities of compounds 1 -6 against VHR<sup>a</sup></span></h3><div class="caption"><p><i>(adapted from Park et al. 2008)</i></p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK50693/table/ml113.t1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml113.t1_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_ml113.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Compound</th><th id="hd_h_ml113.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">%Inhibition at 50 µM</th><th id="hd_h_ml113.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">IC50 (µM))</th><th id="hd_h_ml113.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CID</th><th id="hd_h_ml113.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">SID(s)</th></tr></thead><tbody><tr><td headers="hd_h_ml113.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1</td><td headers="hd_h_ml113.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">82.8</td><td headers="hd_h_ml113.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3.7</td><td headers="hd_h_ml113.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2932059</td><td headers="hd_h_ml113.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">34500079, 4450071</td></tr><tr><td headers="hd_h_ml113.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml113.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">83.5</td><td headers="hd_h_ml113.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">4.7</td><td headers="hd_h_ml113.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1210330</td><td headers="hd_h_ml113.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">51674707, 29248963, 6159808</td></tr><tr><td headers="hd_h_ml113.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3</td><td headers="hd_h_ml113.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">77.2</td><td headers="hd_h_ml113.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">13.9</td><td headers="hd_h_ml113.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td><td headers="hd_h_ml113.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml113.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">4</td><td headers="hd_h_ml113.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">72.1</td><td headers="hd_h_ml113.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">20.0</td><td headers="hd_h_ml113.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td><td headers="hd_h_ml113.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml113.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">5</td><td headers="hd_h_ml113.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">74.1</td><td headers="hd_h_ml113.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">24.2</td><td headers="hd_h_ml113.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td><td headers="hd_h_ml113.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml113.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">6</td><td headers="hd_h_ml113.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">70.9</td><td headers="hd_h_ml113.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">46.5</td><td headers="hd_h_ml113.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td><td headers="hd_h_ml113.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>a</dt><dd><div id="ml113.tfn1"><p class="no_margin">At all concentrations of the inhibitors, the inhibition assay was performed in duplicates</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobml113t2"><div id="ml113.t2" class="table"><h3><span class="label">Table 2</span><span class="title">Inhibitory activities of compounds against VHR<sup>a</sup></span></h3><div class="caption"><p>(adapted from ZHI et al. 2007)</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK50693/table/ml113.t2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml113.t2_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_ml113.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Compound</th><th id="hd_h_ml113.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">%Inhibition at 100 µM</th><th id="hd_h_ml113.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">IC50 (µM))</th></tr></thead><tbody><tr><td headers="hd_h_ml113.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">GATPT</td><td headers="hd_h_ml113.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">95±2</td><td headers="hd_h_ml113.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2.92</td></tr><tr><td headers="hd_h_ml113.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">AP1</td><td headers="hd_h_ml113.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">67±3</td><td headers="hd_h_ml113.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">56.95</td></tr><tr><td headers="hd_h_ml113.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">AP2</td><td headers="hd_h_ml113.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">74±2</td><td headers="hd_h_ml113.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">100.51</td></tr><tr><td headers="hd_h_ml113.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">AP3</td><td headers="hd_h_ml113.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">63±2</td><td headers="hd_h_ml113.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">45.84</td></tr><tr><td headers="hd_h_ml113.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">AP4</td><td headers="hd_h_ml113.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10±2<sup>b</sup></td><td headers="hd_h_ml113.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">26,200</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>b</dt><dd><div id="ml113.tfn2"><p class="no_margin">Compound concentration was 10 mM</p></div></dd></dl></dl></div></div></div></article><article data-type="fig" id="figobml113f2"><div id="ml113.f2" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK50693/bin/ml113f2.jpg" alt="Figure 2. Chemical structures of VHR inhibitors from Shi et al. 2007." /></div><h3><span class="label">Figure 2</span><span class="title">Chemical structures of VHR inhibitors from Shi <i>et al.</i> 2007</span></h3></div></article><article data-type="table-wrap" id="figobml113t3"><div id="ml113.t3" class="table"><h3><span class="label">Table 3</span><span class="title">PubChem Assay Summaries for Probe project</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK50693/table/ml113.t3/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml113.t3_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml113.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">PubChem BioAssay Name</th><th id="hd_h_ml113.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">AIDs</th><th id="hd_h_ml113.t3_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Probe Type</th><th id="hd_h_ml113.t3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Assay Type</th><th id="hd_h_ml113.t3_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Assay Format</th><th id="hd_h_ml113.t3_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Assay Detection & well format</th></tr></thead><tbody><tr><td headers="hd_h_ml113.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">VHR1 Inhibitors – Primary</td><td headers="hd_h_ml113.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1992" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1992</a></td><td headers="hd_h_ml113.t3_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Inhibitor</td><td headers="hd_h_ml113.t3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Primary</td><td headers="hd_h_ml113.t3_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Biochemical</td><td headers="hd_h_ml113.t3_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Absorbance 96-well</td></tr><tr><td headers="hd_h_ml113.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">VHR1 – Confirmatory (CP & DR)</td><td headers="hd_h_ml113.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1992, 2004</td><td headers="hd_h_ml113.t3_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Inhibitor</td><td headers="hd_h_ml113.t3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Confirmatory</td><td headers="hd_h_ml113.t3_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Biochemical</td><td headers="hd_h_ml113.t3_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Absorbance 96-well</td></tr><tr><td headers="hd_h_ml113.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">VHR1 Inhibition – SAR support</td><td headers="hd_h_ml113.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2074" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2074</a></td><td headers="hd_h_ml113.t3_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Inhibitor</td><td headers="hd_h_ml113.t3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Secondary</td><td headers="hd_h_ml113.t3_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Biochemical</td><td headers="hd_h_ml113.t3_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Fluorescence 96-well</td></tr><tr><td headers="hd_h_ml113.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">HePTP Inhibition - SAR</td><td headers="hd_h_ml113.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2082" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2082</a></td><td headers="hd_h_ml113.t3_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Inhibitor</td><td headers="hd_h_ml113.t3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Counterscreen</td><td headers="hd_h_ml113.t3_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Biochemical</td><td headers="hd_h_ml113.t3_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Fluorescence 96-well</td></tr><tr><td headers="hd_h_ml113.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MKP-1 Inhibition– SAR</td><td headers="hd_h_ml113.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2083" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2083</a></td><td headers="hd_h_ml113.t3_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Inhibitor</td><td headers="hd_h_ml113.t3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Counterscreen</td><td headers="hd_h_ml113.t3_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Biochemical</td><td headers="hd_h_ml113.t3_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Fluorescence 96-wells</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobml113t4"><div id="ml113.t4" class="table"><h3><span class="label">Table 4</span><span class="title">Reagents used for the HTS experiments</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK50693/table/ml113.t4/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml113.t4_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml113.t4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Reagents</th><th id="hd_h_ml113.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Supplier/Vendor</th></tr></thead><tbody><tr><td headers="hd_h_ml113.t4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Recombinant VHR (expressed & purified as per ref. <a class="bibr" href="#ml113.r14" rid="ml113.r14">14</a>)</td><td headers="hd_h_ml113.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dr. Tautz’s Lab</td></tr><tr><td headers="hd_h_ml113.t4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">p-Nitrophenyl phosphate (pNPP)</td><td headers="hd_h_ml113.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Sigma (St. Louis, MO)</td></tr><tr><td headers="hd_h_ml113.t4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">BIOMOL GREEN</td><td headers="hd_h_ml113.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">BIOMOL Research Laboratories, Inc. (Plymouth Meeting, PA)</td></tr><tr><td headers="hd_h_ml113.t4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Bis-Tris pH 6.0 reaction buffer</td><td headers="hd_h_ml113.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Sigma (St. Louis, MO)</td></tr><tr><td headers="hd_h_ml113.t4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dithiothreitol (DTT)</td><td headers="hd_h_ml113.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Sigma (St. Louis, MO)</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobml113t5"><div id="ml113.t5" class="table"><h3><span class="label">Table 5</span><span class="title">Most Potent VHR Screening Hits</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK50693/table/ml113.t5/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml113.t5_lrgtbl__"><table class="no_margin"><thead><tr><th id="hd_h_ml113.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">#</th><th id="hd_h_ml113.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">PubChem SID</th><th id="hd_h_ml113.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Structure</th><th id="hd_h_ml113.t5_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">K<sub>i</sub> (µM)</th></tr></thead><tbody><tr><td headers="hd_h_ml113.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml113.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/17460170" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">17460170</a></td><td headers="hd_h_ml113.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50693/bin/ml113fu2.jpg" alt="Image ml113fu2.jpg" /></div></td><td headers="hd_h_ml113.t5_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.809</td></tr><tr><td headers="hd_h_ml113.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml113.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/17467259" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">17467259</a></td><td headers="hd_h_ml113.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50693/bin/ml113fu3.jpg" alt="Image ml113fu3.jpg" /></div></td><td headers="hd_h_ml113.t5_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1.76</td></tr><tr><td headers="hd_h_ml113.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml113.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/17459623" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">17459623</a></td><td headers="hd_h_ml113.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50693/bin/ml113fu4.jpg" alt="Image ml113fu4.jpg" /></div></td><td headers="hd_h_ml113.t5_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1.86</td></tr><tr><td headers="hd_h_ml113.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml113.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/17470230" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">17470230</a></td><td headers="hd_h_ml113.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50693/bin/ml113fu5.jpg" alt="Image ml113fu5.jpg" /></div></td><td headers="hd_h_ml113.t5_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2.01</td></tr><tr><td headers="hd_h_ml113.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5</td><td headers="hd_h_ml113.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/17464133" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">17464133</a></td><td headers="hd_h_ml113.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50693/bin/ml113fu6.jpg" alt="Image ml113fu6.jpg" /></div></td><td headers="hd_h_ml113.t5_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2.09</td></tr><tr><td headers="hd_h_ml113.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6</td><td headers="hd_h_ml113.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/17486385" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">17486385</a></td><td headers="hd_h_ml113.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50693/bin/ml113fu7.jpg" alt="Image ml113fu7.jpg" /></div></td><td headers="hd_h_ml113.t5_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2.64</td></tr><tr><td headers="hd_h_ml113.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">7</td><td headers="hd_h_ml113.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/17462192" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">17462192</a></td><td headers="hd_h_ml113.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50693/bin/ml113fu8.jpg" alt="Image ml113fu8.jpg" /></div></td><td headers="hd_h_ml113.t5_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2.94</td></tr><tr><td headers="hd_h_ml113.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">8</td><td headers="hd_h_ml113.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/17438068" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">17438068</a></td><td headers="hd_h_ml113.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50693/bin/ml113fu9.jpg" alt="Image ml113fu9.jpg" /></div></td><td headers="hd_h_ml113.t5_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3.07</td></tr><tr><td headers="hd_h_ml113.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">9</td><td headers="hd_h_ml113.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/17484886" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">17484886</a></td><td headers="hd_h_ml113.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50693/bin/ml113fu10.jpg" alt="Image ml113fu10.jpg" /></div></td><td headers="hd_h_ml113.t5_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3.13</td></tr><tr><td headers="hd_h_ml113.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">10</td><td headers="hd_h_ml113.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/17464668" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">17464668</a></td><td headers="hd_h_ml113.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50693/bin/ml113fu11.jpg" alt="Image ml113fu11.jpg" /></div></td><td headers="hd_h_ml113.t5_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3.19</td></tr><tr><td headers="hd_h_ml113.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">11</td><td headers="hd_h_ml113.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/17457520" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">17457520</a></td><td headers="hd_h_ml113.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50693/bin/ml113fu12.jpg" alt="Image ml113fu12.jpg" /></div></td><td headers="hd_h_ml113.t5_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3.49</td></tr><tr><td headers="hd_h_ml113.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">12</td><td headers="hd_h_ml113.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/17468205" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">17468205</a></td><td headers="hd_h_ml113.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50693/bin/ml113fu13.jpg" alt="Image ml113fu13.jpg" /></div></td><td headers="hd_h_ml113.t5_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3.87</td></tr><tr><td headers="hd_h_ml113.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">13</td><td headers="hd_h_ml113.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/17462864" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">17462864</a></td><td headers="hd_h_ml113.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50693/bin/ml113fu14.jpg" alt="Image ml113fu14.jpg" /></div></td><td headers="hd_h_ml113.t5_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4.44</td></tr><tr><td headers="hd_h_ml113.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">14</td><td headers="hd_h_ml113.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/17474557" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">17474557</a></td><td headers="hd_h_ml113.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50693/bin/ml113fu15.jpg" alt="Image ml113fu15.jpg" /></div></td><td headers="hd_h_ml113.t5_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1.21</td></tr><tr><td headers="hd_h_ml113.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">15</td><td headers="hd_h_ml113.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/17465980" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">17465980</a></td><td headers="hd_h_ml113.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50693/bin/ml113fu16.jpg" alt="Image ml113fu16.jpg" /></div></td><td headers="hd_h_ml113.t5_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">12.8</td></tr><tr><td headers="hd_h_ml113.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">16</td><td headers="hd_h_ml113.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/17437417" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">17437417</a></td><td headers="hd_h_ml113.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50693/bin/ml113fu17.jpg" alt="Image ml113fu17.jpg" /></div></td><td headers="hd_h_ml113.t5_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">13.4</td></tr><tr><td headers="hd_h_ml113.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">17</td><td headers="hd_h_ml113.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/17444164" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">17444164</a></td><td headers="hd_h_ml113.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50693/bin/ml113fu18.jpg" alt="Image ml113fu18.jpg" /></div></td><td headers="hd_h_ml113.t5_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">13.8</td></tr><tr><td headers="hd_h_ml113.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">18</td><td headers="hd_h_ml113.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/17461020" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">17461020</a></td><td headers="hd_h_ml113.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50693/bin/ml113fu19.jpg" alt="Image ml113fu19.jpg" /></div></td><td headers="hd_h_ml113.t5_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">13.8</td></tr><tr><td headers="hd_h_ml113.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">19</td><td headers="hd_h_ml113.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/17464863" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">17464863</a></td><td headers="hd_h_ml113.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50693/bin/ml113fu20.jpg" alt="Image ml113fu20.jpg" /></div></td><td headers="hd_h_ml113.t5_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">15.8</td></tr><tr><td headers="hd_h_ml113.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20</td><td headers="hd_h_ml113.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/17460326" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">17460326</a></td><td headers="hd_h_ml113.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50693/bin/ml113fu21.jpg" alt="Image ml113fu21.jpg" /></div></td><td headers="hd_h_ml113.t5_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">15.9</td></tr><tr><td headers="hd_h_ml113.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">21</td><td headers="hd_h_ml113.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/17466330" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">17466330</a></td><td headers="hd_h_ml113.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50693/bin/ml113fu22.jpg" alt="Image ml113fu22.jpg" /></div></td><td headers="hd_h_ml113.t5_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">16.2</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div id="ml113.tfn3"><p class="no_margin">K<sub>i</sub> value < 20 µM. Compounds <b>11</b>, <b>13</b>, <b>19</b>, and <b>21</b> are mixtures of <i>E/Z</i>-isomers.</p></div></dd></dl></dl></div></div></div></article><article data-type="fig" id="figobml113f3"><div id="ml113.f3" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK50693/bin/ml113f3.jpg" alt="Figure 3. Profiling of the 21 most active VHR screening hits at 20 µM against VHR (AID-2074) & HePTP (AID-2082)." /></div><h3><span class="label">Figure 3</span><span class="title">Profiling of the 21 most active VHR screening hits at 20 µM against VHR (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2074" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2074</a>) &
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HePTP (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2082" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2082</a>)</span></h3><div class="caption"><p>Asterisks indicate compounds 1, 8, and 18 (<a class="figpopup" href="/books/NBK50693/table/ml113.t5/?report=objectonly" target="object" rid-figpopup="figml113t5" rid-ob="figobml113t5">Table 5</a>), which appeared to be selectively inhibiting VHR without HePTP inhibition</p></div></div></article><article data-type="fig" id="figobml113f4"><div id="ml113.f4" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK50693/bin/ml113f4.jpg" alt="Figure 4. Characterization of SID-17460170 (1)." /></div><h3><span class="label">Figure 4</span><span class="title">Characterization of <a href="https://pubchem.ncbi.nlm.nih.gov/substance/17460170" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-17460170</a>
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<b>(1).</b></span></h3><div class="caption"><p>(A) Michaelis-Menten kinetic
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measurements, Lineweaver-Burk plots for <a href="https://pubchem.ncbi.nlm.nih.gov/substance/17460170" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-17460170</a>
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<b>(1)</b> with VHR. (B) FlexX docking of <a href="https://pubchem.ncbi.nlm.nih.gov/substance/17460170" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-17460170</a>
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<b>(1)</b> into the active site of VHR crystal structure (PDB code 1J4X). The color code of the MOLCAD surface represents the lipophilic potential (brown: most hydrophobic, blue: most hydrophilic)</p></div></div></article><article data-type="fig" id="figobml113fu2"><div id="ml113.fu2" class="figure"><div class="graphic"><img data-src="/books/NBK50693/bin/ml113fu23.jpg" alt="Image ml113fu23" /></div></div></article><article data-type="table-wrap" id="figobml113t6"><div id="ml113.t6" class="table"><h3><span class="label">Table 6</span><span class="title"><i>In vitro</i> potency and Selectivity of 1-phenylpyrazole VHR inhibitor analogs</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK50693/table/ml113.t6/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml113.t6_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml113.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">ID MLS- Internal No. (SA1#)</th><th id="hd_h_ml113.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Structure R =</th><th id="hd_h_ml113.t6_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">PubChem SID</th><th id="hd_h_ml113.t6_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">PubChem CID</th><th id="hd_h_ml113.t6_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">VHR IC<sub>50</sub> (µM) <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2074" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2074</a></th><th id="hd_h_ml113.t6_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MKP-1 IC<sub>50</sub> (µM)<br /><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2083" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2083</a></th><th id="hd_h_ml113.t6_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">HePTP IC<sub>50</sub> (µM)<br /><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2082" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2082</a></th></tr></thead><tbody><tr><td headers="hd_h_ml113.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0425632 <b>(SA1)</b></td><td headers="hd_h_ml113.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50693/bin/ml113fu24.jpg" alt="Image ml113fu24.jpg" /></div></td><td headers="hd_h_ml113.t6_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85256223" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85256223</a></td><td headers="hd_h_ml113.t6_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6161281</td><td headers="hd_h_ml113.t6_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.018</td><td headers="hd_h_ml113.t6_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.46</td><td headers="hd_h_ml113.t6_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.62</td></tr><tr><td headers="hd_h_ml113.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0425633 <b>(SA2)</b></td><td headers="hd_h_ml113.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50693/bin/ml113fu25.jpg" alt="Image ml113fu25.jpg" /></div></td><td headers="hd_h_ml113.t6_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85256224" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85256224</a></td><td headers="hd_h_ml113.t6_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6274486</td><td headers="hd_h_ml113.t6_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.071</td><td headers="hd_h_ml113.t6_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.47</td><td headers="hd_h_ml113.t6_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1.2</td></tr><tr><td headers="hd_h_ml113.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0425634 <b>(SA3)</b></td><td headers="hd_h_ml113.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50693/bin/ml113fu26.jpg" alt="Image ml113fu26.jpg" /></div></td><td headers="hd_h_ml113.t6_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85256225" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85256225</a></td><td headers="hd_h_ml113.t6_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5932584</td><td headers="hd_h_ml113.t6_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.074</td><td headers="hd_h_ml113.t6_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.52</td><td headers="hd_h_ml113.t6_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.87</td></tr><tr><td headers="hd_h_ml113.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0425635 <b>(SA4)</b></td><td headers="hd_h_ml113.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50693/bin/ml113fu27.jpg" alt="Image ml113fu27.jpg" /></div></td><td headers="hd_h_ml113.t6_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85256226" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85256226</a></td><td headers="hd_h_ml113.t6_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5998084</td><td headers="hd_h_ml113.t6_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.078</td><td headers="hd_h_ml113.t6_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.78</td><td headers="hd_h_ml113.t6_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1.5</td></tr><tr><td headers="hd_h_ml113.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0425636 <b>(SA5)</b></td><td headers="hd_h_ml113.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50693/bin/ml113fu28.jpg" alt="Image ml113fu28.jpg" /></div></td><td headers="hd_h_ml113.t6_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85256227" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85256227</a></td><td headers="hd_h_ml113.t6_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6166563</td><td headers="hd_h_ml113.t6_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.27</td><td headers="hd_h_ml113.t6_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2.8</td><td headers="hd_h_ml113.t6_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2.4</td></tr><tr><td headers="hd_h_ml113.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0425637 <b>(SA6)</b></td><td headers="hd_h_ml113.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CH<sub>3</sub></td><td headers="hd_h_ml113.t6_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85256228" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85256228</a></td><td headers="hd_h_ml113.t6_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6001181</td><td headers="hd_h_ml113.t6_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3.1</td><td headers="hd_h_ml113.t6_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">ND</td><td headers="hd_h_ml113.t6_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">ND</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobml113fu3"><div id="ml113.fu3" class="figure"><div class="graphic"><img data-src="/books/NBK50693/bin/ml113fu29.jpg" alt="Image ml113fu29" /></div></div></article><article data-type="fig" id="figobml113fu4"><div id="ml113.fu4" class="figure"><div class="graphic"><img data-src="/books/NBK50693/bin/ml113fu30.jpg" alt="Image ml113fu30" /></div></div></article><article data-type="fig" id="figobml113fu5"><div id="ml113.fu5" class="figure"><div class="graphic"><img data-src="/books/NBK50693/bin/ml113fu31.jpg" alt="Image ml113fu31" /></div></div></article><article data-type="table-wrap" id="figobml113t7"><div id="ml113.t7" class="table"><h3><span class="label">Table 7</span><span class="title">Submission of Probe and 5 analogs to the MLSMR</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK50693/table/ml113.t7/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml113.t7_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml113.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Probe/Analog</th><th id="hd_h_ml113.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS# (DPI)</th><th id="hd_h_ml113.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-# (BCCG#)</th><th id="hd_h_ml113.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SID</th><th id="hd_h_ml113.t7_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID</th><th id="hd_h_ml113.t7_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Source (vendor or BCCG syn)</th><th id="hd_h_ml113.t7_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Amt (mg)</th><th id="hd_h_ml113.t7_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Date submitted</th></tr></thead><tbody><tr><td headers="hd_h_ml113.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Probe<br /><b><a href="/pcsubstance/?term=ML113[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML113</a></b></td><td headers="hd_h_ml113.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS002554749</td><td headers="hd_h_ml113.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0425632</td><td headers="hd_h_ml113.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85256223" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85256223</a></td><td headers="hd_h_ml113.t7_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6161281</td><td headers="hd_h_ml113.t7_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">PrincetonBio</td><td headers="hd_h_ml113.t7_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">50</td><td headers="hd_h_ml113.t7_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">10/16/09</td></tr><tr><td headers="hd_h_ml113.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Analog1</td><td headers="hd_h_ml113.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS002554750</td><td headers="hd_h_ml113.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0425633</td><td headers="hd_h_ml113.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85256224" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85256224</a></td><td headers="hd_h_ml113.t7_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6274486</td><td headers="hd_h_ml113.t7_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">PrincetonBio</td><td headers="hd_h_ml113.t7_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20</td><td headers="hd_h_ml113.t7_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">10/16/09</td></tr><tr><td headers="hd_h_ml113.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Analog2</td><td headers="hd_h_ml113.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS002554751</td><td headers="hd_h_ml113.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0425634</td><td headers="hd_h_ml113.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85256225" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85256225</a></td><td headers="hd_h_ml113.t7_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5932584</td><td headers="hd_h_ml113.t7_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">PrincetonBio</td><td headers="hd_h_ml113.t7_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20</td><td headers="hd_h_ml113.t7_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">10/16/09</td></tr><tr><td headers="hd_h_ml113.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Analog3</td><td headers="hd_h_ml113.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS002554752</td><td headers="hd_h_ml113.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0425635</td><td headers="hd_h_ml113.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85256226" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85256226</a></td><td headers="hd_h_ml113.t7_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5998084</td><td headers="hd_h_ml113.t7_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">PrincetonBio</td><td headers="hd_h_ml113.t7_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20</td><td headers="hd_h_ml113.t7_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">10/16/09</td></tr><tr><td headers="hd_h_ml113.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Analog4</td><td headers="hd_h_ml113.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS002554753</td><td headers="hd_h_ml113.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0425636</td><td headers="hd_h_ml113.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85256227" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85256227</a></td><td headers="hd_h_ml113.t7_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6166563</td><td headers="hd_h_ml113.t7_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">PrincetonBio</td><td headers="hd_h_ml113.t7_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20</td><td headers="hd_h_ml113.t7_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">10/16/09</td></tr><tr><td headers="hd_h_ml113.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Analog5</td><td headers="hd_h_ml113.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS002554754</td><td headers="hd_h_ml113.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0425637</td><td headers="hd_h_ml113.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85256228" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85256228</a></td><td headers="hd_h_ml113.t7_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6001181</td><td headers="hd_h_ml113.t7_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">PrincetonBio</td><td headers="hd_h_ml113.t7_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20</td><td headers="hd_h_ml113.t7_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">10/16/09</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobml113f5"><div id="ml113.f5" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK50693/bin/ml113f5.jpg" alt="Figure 4. Effects of VHR inhibitors on proliferation and survival of cervix cancer cells." /></div><h3><span class="label">Figure 4</span><span class="title">Effects of VHR inhibitors on proliferation and survival of cervix cancer cells</span></h3><div class="caption"><p>(A)
|
|
Cell numbers of HeLa cervix carcinoma cells and normal keratinocytes (NK) after 24 h of treatment with 20 µM inhibitors, given as percentage of the DMSO control. (B,C) [3H]-Thymidine incorporation assay with 20 µM inhibitors or vehicle (DMSO) in HeLa (B) or Caski (C) cervix cancer carcinoma cells. (D) Survival/death of HeLa and CasKi cells in presence of 20 µM inhibitors or DMSO after 24 h, evaluated by Annexin V FITC/PI flow cytometry assay (FACS Vantage, BD). Percentage of live cells (Annexin V negative and PI negative cells on flow cytometry dot plots) is given. All data are reported as mean ± SD from three independent experiments. (see ref. <a class="bibr" href="#ml113.r18" rid="ml113.r18">18</a>)</p></div></div></article><article data-type="table-wrap" id="figobml113t8"><div id="ml113.t8" class="table"><h3><span class="label">Table 8</span><span class="title">Summary of <i>in vitro</i> ADMET/PK Properties of HePTP Inhibitor Probe</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK50693/table/ml113.t8/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml113.t8_lrgtbl__"><table class="no_margin"><thead><tr><th id="hd_h_ml113.t8_1_1_1_1" rowspan="2" colspan="1" headers="hd_h_ml113.t8_1_1_1_1" style="text-align:center;vertical-align:top;">Probe CID<br />Probe ML#<br />BCCG MLS-#</th><th id="hd_h_ml113.t8_1_1_1_2" rowspan="2" colspan="1" headers="hd_h_ml113.t8_1_1_1_2" style="text-align:center;vertical-align:top;">Aqueous Solubility<br />(μg/mL)<sup>a</sup> (@ pH)</th><th id="hd_h_ml113.t8_1_1_1_3" rowspan="2" colspan="1" headers="hd_h_ml113.t8_1_1_1_3" style="text-align:center;vertical-align:top;">PAMPA Pe<br />(×10<sup>−6</sup> cm/s)<sup>b</sup> (@ pH)</th><th id="hd_h_ml113.t8_1_1_1_4" colspan="2" rowspan="1" style="text-align:center;vertical-align:top;">Plasma Protein Binding (% Bound)</th><th id="hd_h_ml113.t8_1_1_1_5" rowspan="2" colspan="1" headers="hd_h_ml113.t8_1_1_1_5" style="text-align:center;vertical-align:top;">Plasma Stability<sup>c</sup><br />Human Mouse/</th><th id="hd_h_ml113.t8_1_1_1_6" rowspan="2" colspan="1" headers="hd_h_ml113.t8_1_1_1_6" style="text-align:center;vertical-align:top;">Hepatic Microsome Stability<sup>d</sup><br />Human/Mouse</th><th id="hd_h_ml113.t8_1_1_1_7" rowspan="2" colspan="1" headers="hd_h_ml113.t8_1_1_1_7" style="text-align:center;vertical-align:top;">Hepatic Toxicity<sup>e</sup><br />LC50 (μM)</th></tr><tr><th headers="hd_h_ml113.t8_1_1_1_4" id="hd_h_ml113.t8_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Human<br />1μM/10μM</th><th headers="hd_h_ml113.t8_1_1_1_4" id="hd_h_ml113.t8_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Mouse<br />1μM/10μM</th></tr></thead><tbody><tr><td headers="hd_h_ml113.t8_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID6161281</td><td headers="hd_h_ml113.t8_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.16 (5.0)</td><td headers="hd_h_ml113.t8_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><0.8 (5.0)</td><td headers="hd_h_ml113.t8_1_1_1_4 hd_h_ml113.t8_1_1_2_1" rowspan="3" colspan="1" style="text-align:center;vertical-align:middle;">98.28/99.83</td><td headers="hd_h_ml113.t8_1_1_1_4 hd_h_ml113.t8_1_1_2_2" rowspan="3" colspan="1" style="text-align:center;vertical-align:middle;">84.59/70.16</td><td headers="hd_h_ml113.t8_1_1_1_5" rowspan="3" colspan="1" style="text-align:center;vertical-align:middle;">87.89/100</td><td headers="hd_h_ml113.t8_1_1_1_6" rowspan="3" colspan="1" style="text-align:center;vertical-align:middle;">57.85/51.84</td><td headers="hd_h_ml113.t8_1_1_1_7" rowspan="3" colspan="1" style="text-align:center;vertical-align:middle;">>50</td></tr><tr><td headers="hd_h_ml113.t8_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b><a href="/pcsubstance/?term=ML113[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML113</a></b></td><td headers="hd_h_ml113.t8_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.46 (6.2)</td><td headers="hd_h_ml113.t8_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><0.8 (6.2)</td></tr><tr><td headers="hd_h_ml113.t8_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0425632</td><td headers="hd_h_ml113.t8_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.65 (7.4)</td><td headers="hd_h_ml113.t8_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><0.9 (7.4)</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>a</dt><dd><div id="ml113.tfn4"><p class="no_margin">in aqueous buffer, pH’s 5.0/6.2/7.4</p></div></dd></dl><dl class="bkr_refwrap"><dt>b</dt><dd><div id="ml113.tfn5"><p class="no_margin">in aqueous buffer; Donor compartment pH’s 5.0/6.2/7.4; Acceptor compartment pH 7.4</p></div></dd></dl><dl class="bkr_refwrap"><dt>c</dt><dd><div id="ml113.tfn6"><p class="no_margin">% remaining at 3 hr</p></div></dd></dl><dl class="bkr_refwrap"><dt>d</dt><dd><div id="ml113.tfn7"><p class="no_margin">% remaining at 1 hr</p></div></dd></dl><dl class="bkr_refwrap"><dt>e</dt><dd><div id="ml113.tfn8"><p class="no_margin">towards Fa2N-4 immortalized human hepatocytes</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobml113t9"><div id="ml113.t9" class="table"><h3><span class="label">Table 9</span><span class="title">Properties computed from Structure</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK50693/table/ml113.t9/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml113.t9_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml113.t9_1_1_1_1" colspan="2" rowspan="1" style="text-align:center;vertical-align:bottom;">CID6161281 [<a href="/pcsubstance/?term=ML113[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML113</a>] (MLS-0425632)</th></tr></thead><tbody><tr><td headers="hd_h_ml113.t9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Molecular Weight [g/mol]</td><td headers="hd_h_ml113.t9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">612.13938</td></tr><tr><td headers="hd_h_ml113.t9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Molecular formula</td><td headers="hd_h_ml113.t9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">C<sub>28</sub>H<sub>22</sub>ClN<sub>3</sub>O<sub>5</sub>S<sub>3</sub></td></tr><tr><td headers="hd_h_ml113.t9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">XLogP3-AA</td><td headers="hd_h_ml113.t9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">5.6</td></tr><tr><td headers="hd_h_ml113.t9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H-Bond Donor</td><td headers="hd_h_ml113.t9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1</td></tr><tr><td headers="hd_h_ml113.t9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H-Bond Acceptor</td><td headers="hd_h_ml113.t9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">6</td></tr><tr><td headers="hd_h_ml113.t9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Rotatable Bond Count</td><td headers="hd_h_ml113.t9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">9</td></tr><tr><td headers="hd_h_ml113.t9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Exact Mass</td><td headers="hd_h_ml113.t9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">611.041011</td></tr><tr><td headers="hd_h_ml113.t9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MonoIsotopic Mass</td><td headers="hd_h_ml113.t9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">611.041011</td></tr><tr><td headers="hd_h_ml113.t9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Topological Polar Surface Area</td><td headers="hd_h_ml113.t9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">168</td></tr><tr><td headers="hd_h_ml113.t9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Heavy Atom Count</td><td headers="hd_h_ml113.t9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">40</td></tr><tr><td headers="hd_h_ml113.t9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Formal Charge</td><td headers="hd_h_ml113.t9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml113.t9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Complexity</td><td headers="hd_h_ml113.t9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1030</td></tr><tr><td headers="hd_h_ml113.t9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Isotope Atom Count</td><td headers="hd_h_ml113.t9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml113.t9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Defined Atom StereoCenter Count</td><td headers="hd_h_ml113.t9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml113.t9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Undefined Atom StereoCenter Count</td><td headers="hd_h_ml113.t9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml113.t9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Defined Bond StereoCenter Count</td><td headers="hd_h_ml113.t9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1</td></tr><tr><td headers="hd_h_ml113.t9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Undefined Bond StereoCenter Count</td><td headers="hd_h_ml113.t9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml113.t9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Covalently-Bonded Unit Count</td><td headers="hd_h_ml113.t9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1</td></tr></tbody></table></div></div></article></div><div id="jr-scripts"><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/libs.min.js"> </script><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.min.js"> </script><script type="text/javascript" src="/core/mathjax/2.7.9/MathJax.js?config=TeX-AMS-MML_SVG"> </script></div></div>
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