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<meta name="robots" content="INDEX,FOLLOW,NOARCHIVE" /><meta name="citation_inbook_title" content="Probe Reports from the NIH Molecular Libraries Program [Internet]" /><meta name="citation_title" content="Probe Report for P97/cdc48 Inhibitors" /><meta name="citation_publisher" content="National Center for Biotechnology Information (US)" /><meta name="citation_date" content="2010/08/06" /><meta name="citation_author" content="SJ Brown" /><meta name="citation_author" content="T-F Chou" /><meta name="citation_author" content="R Deshaies" /><meta name="citation_author" content="E Roberts" /><meta name="citation_author" content="M Guerrero" /><meta name="citation_author" content="D Minond" /><meta name="citation_author" content="BA Mercer" /><meta name="citation_author" content="P Hodder" /><meta name="citation_author" content="HR Rosen" /><meta name="citation_pmid" content="21433362" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK47346/" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="Probe Report for P97/cdc48 Inhibitors" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="National Center for Biotechnology Information (US)" /><meta name="DC.Contributor" content="SJ Brown" /><meta name="DC.Contributor" content="T-F Chou" /><meta name="DC.Contributor" content="R Deshaies" /><meta name="DC.Contributor" content="E Roberts" /><meta name="DC.Contributor" content="M Guerrero" /><meta name="DC.Contributor" content="D Minond" /><meta name="DC.Contributor" content="BA Mercer" /><meta name="DC.Contributor" content="P Hodder" /><meta name="DC.Contributor" content="HR Rosen" /><meta name="DC.Date" content="2010/08/06" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK47346/" /><meta name="description" content="The highly conserved p97 ATPase functions in endoplasmic reticulum-associated degradation (ERAD) by hydrolyzing ATP needed to export ubiquitinated substrates to the cytosol for degradation by the proteasome. Inhibition of p97 leads to unfolded protein accumulation, and ultimately, cell death. The discovery of p97 missense mutations in a genetic form of human dementia, in addition to the localization of p97 in ubiquitylated inclusions in affected neurons of amyotrophic lateral sclerosis and Parkinson's disease, and the overproduction of p97 in multiple cancers suggests that p97 has diverse and essential cellular roles. Thus, the identification of probes that selectively target p97 activity would be useful for providing insights into the biological roles of P97. The probe ML080 (CID-25110544) is the first cell active, reversible inhibitor of P97. This compound in the ATP-depletion-based assay, is cell penetrable as demonstrated by activity in the cell-based ubiquitin-GFP turnover assay." /><meta name="og:title" content="Probe Report for P97/cdc48 Inhibitors" /><meta name="og:type" content="book" /><meta name="og:description" content="The highly conserved p97 ATPase functions in endoplasmic reticulum-associated degradation (ERAD) by hydrolyzing ATP needed to export ubiquitinated substrates to the cytosol for degradation by the proteasome. Inhibition of p97 leads to unfolded protein accumulation, and ultimately, cell death. The discovery of p97 missense mutations in a genetic form of human dementia, in addition to the localization of p97 in ubiquitylated inclusions in affected neurons of amyotrophic lateral sclerosis and Parkinson's disease, and the overproduction of p97 in multiple cancers suggests that p97 has diverse and essential cellular roles. Thus, the identification of probes that selectively target p97 activity would be useful for providing insights into the biological roles of P97. The probe ML080 (CID-25110544) is the first cell active, reversible inhibitor of P97. 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<div class="pre-content"><div><div class="bk_prnt"><p class="small">NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.</p><p>Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010-. </p></div><div class="iconblock clearfix whole_rhythm no_top_margin bk_noprnt"><a class="img_link icnblk_img" title="Table of Contents Page" href="/books/n/mlprobe/"><img class="source-thumb" src="/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-mlprobe-lrg.png" alt="Cover of Probe Reports from the NIH Molecular Libraries Program" height="100px" width="80px" /></a><div class="icnblk_cntnt eight_col"><h2>Probe Reports from the NIH Molecular Libraries Program [Internet].</h2><a data-jig="ncbitoggler" href="#__NBK47346_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK47346_dtls__"><div>Bethesda (MD): National Center for Biotechnology Information (US); 2010-.</div></div><div class="half_rhythm"><ul class="inline_list"><li style="margin-right:1em"><a class="bk_cntns" href="/books/n/mlprobe/">Contents</a></li></ul></div><div class="bk_noprnt"><form method="get" action="/books/n/mlprobe/" id="bk_srch"><div class="bk_search"><label for="bk_term" class="offscreen_noflow">Search term</label><input type="text" title="Search this book" id="bk_term" name="term" value="" data-jig="ncbiclearbutton" /> <input type="submit" class="jig-ncbibutton" value="Search this book" submit="false" style="padding: 0.1em 0.4em;" /></div></form></div></div><div class="icnblk_cntnt two_col"><div class="pagination bk_noprnt"><a class="active page_link prev" href="/books/n/mlprobe/ml081/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/mlprobe/ml079/" title="Next page in this title">Next ></a></div></div></div></div></div>
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<div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><h1 id="_NBK47346_"><span class="title" itemprop="name">Probe Report for P97/cdc48 Inhibitors</span></h1><p class="contrib-group"><span itemprop="author">SJ Brown</span>, <span itemprop="author">T-F Chou</span>, <span itemprop="author">R Deshaies</span>, <span itemprop="author">E Roberts</span>, <span itemprop="author">M Guerrero</span>, <span itemprop="author">D Minond</span>, <span itemprop="author">BA Mercer</span>, <span itemprop="author">P Hodder</span>, and <span itemprop="author">HR Rosen</span>.</p><p class="small">Received: <span itemprop="datePublished">March 6, 2009</span>; Last Update: <span itemprop="dateModified">August 6, 2010</span>.</p></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="_abs_rndgid_" itemprop="description"><p>The highly conserved p97 ATPase functions in endoplasmic reticulum-associated degradation (ERAD) by hydrolyzing ATP needed to export ubiquitinated substrates to the cytosol for degradation by the proteasome. Inhibition of p97 leads to unfolded protein accumulation, and ultimately, cell death. The discovery of p97 missense mutations in a genetic form of human dementia, in addition to the localization of p97 in ubiquitylated inclusions in affected neurons of amyotrophic lateral sclerosis and Parkinson's disease, and the overproduction of p97 in multiple cancers suggests that p97 has diverse and essential cellular roles. Thus, the identification of probes that selectively target p97 activity would be useful for providing insights into the biological roles of P97. The probe ML080 (CID-25110544) is the first cell active, reversible inhibitor of P97. This compound in the ATP-depletion-based assay, is cell penetrable as demonstrated by activity in the cell-based ubiquitin-GFP turnover assay.</p></div><div class="h2"></div><p><b>Assigned Assay Grant #:</b> 1 R03 MH085687-01</p><p><b>Screening Center Name & PI:</b> Scripps Research Institute Molecular
|
||
Screening Center, H. Rosen, P. Hodder</p><p><b>Chemistry Center Name & PI:</b> Scripps Research Institute Molecular
|
||
Screening Center, Scripps Research Institute Molecular Screening Center, H. Rosen, W.
|
||
Roush</p><p><b>Assay Submitter & Institution:</b> Raymond Deshaies, California
|
||
Institute of Technology (Caltech)</p><p><b>PubChem Summary Bioassay Identifier (AID):</b>
|
||
<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1794" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1794</a></p><div id="ml080.s1"><h2 id="_ml080_s1_">Probe Structure & Characteristics</h2><p>This compound CID-25110544 has a 2-amino thiazole core and met the probe definition
|
||
criteria for this P97 Inhibitor project. This compound in the ATP-depletion-based
|
||
assay, is cell penetrant as demonstrated by activity in the cell-based Ub-GFP
|
||
turnover assay. The structure of the compound, CID-25110544 (CYM-5654), which met
|
||
probe selection criteria, is indicated in the box below.</p><div id="ml080.fu1" class="figure"><div class="graphic"><img src="/books/NBK47346/bin/ml080fu1.jpg" alt="Image ml080fu1" /></div></div><div id="ml080.tu1" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK47346/table/ml080.tu1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml080.tu1_lrgtbl__"><table><thead><tr><th id="hd_h_ml080.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CID/ML</th><th id="hd_h_ml080.tu1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">SID</th><th id="hd_h_ml080.tu1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Target Name</th><th id="hd_h_ml080.tu1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Target IC<sub>50</sub>
|
||
[AID]</th><th id="hd_h_ml080.tu1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Anti-target</th><th id="hd_h_ml080.tu1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Anti-target IC<sub>50</sub>
|
||
[AID]</th><th id="hd_h_ml080.tu1_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Selectivity</th><th id="hd_h_ml080.tu1_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Secondary Assay: Ub-GFP Assay
|
||
IC<sub>50</sub> [AID]</th></tr></thead><tbody><tr><td headers="hd_h_ml080.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"> CID-25110544/<a href="/pcsubstance/?term=ML080[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML080</a>
|
||
</td><td headers="hd_h_ml080.tu1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
|
||
<a href="https://pubchem.ncbi.nlm.nih.gov/substance/56432669" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-56432669</a>
|
||
</td><td headers="hd_h_ml080.tu1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"> P97 ATPase </td><td headers="hd_h_ml080.tu1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"> 4.5 μM
|
||
[<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1534" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1534</a>] </td><td headers="hd_h_ml080.tu1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"> Mutant P97C522A </td><td headers="hd_h_ml080.tu1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"> >50 μM
|
||
[<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1551" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1551</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1629" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1629</a>] </td><td headers="hd_h_ml080.tu1_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"> >10 </td><td headers="hd_h_ml080.tu1_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"> 7.5 μM refer to Summary
|
||
AID (TBD) </td></tr></tbody></table></div></div></div><div id="ml080.s2"><h2 id="_ml080_s2_">Recommendations for the scientific use of this probe</h2><p>This compound is useful for biochemical and cell-based assays in which it is
|
||
desirable to specifically block p97 activity. Inhibition of p97 leads to unfolded
|
||
protein accumulation, and ultimately cell death. This probe is the first cell
|
||
active, reversible inhibitor of P97.</p></div><div id="ml080.s3"><h2 id="_ml080_s3_">1. Scientific Rationale for Project</h2><p>Misfolded proteins accumulate in the endoplasmic reticulum (ER) in response to
|
||
environmental stress(<a class="bk_pop" href="#ml080.r1">1</a>). To reduce the
|
||
burden these proteins place on the secretory pathway, eukaryotic cells have evolved
|
||
a process, known as ER-associated degradation (ERAD), to recognize and eliminate
|
||
these proteins (<a class="bk_pop" href="#ml080.r1">1</a>, <a class="bk_pop" href="#ml080.r2">2</a>). The highly conserved p97 ATPase functions in ERAD by
|
||
hydrolyzing ATP needed to export ubiquitinated substrates to the cytosol for
|
||
degradation by the proteasome (<a class="bk_pop" href="#ml080.r2">2</a>, <a class="bk_pop" href="#ml080.r3">3</a>). The discovery of p97 missense
|
||
mutations in a genetic form of human dementia (<a class="bk_pop" href="#ml080.r4" data-bk-pop-others="ml080.r5 ml080.r6">4–6</a>), the
|
||
localization of p97 in ubiquitylated inclusions in affected neurons of amyotrophic
|
||
lateral sclerosis (ALS) and Parkinson’s disease (<a class="bk_pop" href="#ml080.r8" data-bk-pop-others="ml080.r9">8–9</a>), and the
|
||
overproduction of p97 in multiple cancers (10–14), suggests that p97 has
|
||
diverse and essential cellular roles. Thus, the identification of probes that
|
||
selectively target p97 activity may provide insights into the biological roles of
|
||
P97.</p></div><div id="ml080.s4"><h2 id="_ml080_s4_">2. Project Description</h2><div id="ml080.assayinf"><h3>a. Information for each assay implemented and screening run</h3><div id="ml080.pcbaname"><h4>i. PubChem Bioassay Name, AID, Assay-Type (Primary, DR CS,
|
||
Secondary)</h4><div id="ml080.t1" class="table"><h3><span class="label">Table 2</span><span class="title">PubChem BioAssay</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK47346/table/ml080.t1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml080.t1_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml080.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">AID</th><th id="hd_h_ml080.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Assay Name</th><th id="hd_h_ml080.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Assay Type</th><th id="hd_h_ml080.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Target</th><th id="hd_h_ml080.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Powder Sample</th><th id="hd_h_ml080.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Compound Concentration</th></tr></thead><tbody><tr><td headers="hd_h_ml080.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1481" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1481</a></td><td headers="hd_h_ml080.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Primary biochemical
|
||
high-throughput screening assay to measure P97 ATPase
|
||
inhibition</td><td headers="hd_h_ml080.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Primary Assay
|
||
(1X% INH)</td><td headers="hd_h_ml080.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P97</td><td headers="hd_h_ml080.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">No</td><td headers="hd_h_ml080.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">8 μM</td></tr><tr><td headers="hd_h_ml080.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1517" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1517</a></td><td headers="hd_h_ml080.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Confirmation biochemical
|
||
high-throughput screening assay to measure P97 ATPase
|
||
inhibition</td><td headers="hd_h_ml080.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Confirmation Assay
|
||
(3X% INH)</td><td headers="hd_h_ml080.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P97</td><td headers="hd_h_ml080.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">No</td><td headers="hd_h_ml080.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">8 μM</td></tr><tr><td headers="hd_h_ml080.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1534" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1534</a></td><td headers="hd_h_ml080.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Dose Response biochemical
|
||
assay to measure P97 ATPase inhibition</td><td headers="hd_h_ml080.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Dose Response Assay</td><td headers="hd_h_ml080.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P97</td><td headers="hd_h_ml080.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">No</td><td headers="hd_h_ml080.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">10-point, 1:3 dilution
|
||
starting at 50 μM</td></tr><tr><td headers="hd_h_ml080.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1544" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1544</a></td><td headers="hd_h_ml080.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Dose Response biochemical
|
||
assay to measure C522A mutant P97 ATPase inhibition</td><td headers="hd_h_ml080.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Dose Response Assay</td><td headers="hd_h_ml080.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P97 C522A mutant</td><td headers="hd_h_ml080.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">No</td><td headers="hd_h_ml080.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">10-point, 1:3 dilution
|
||
starting at 50 μM</td></tr><tr><td headers="hd_h_ml080.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1551" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1551</a></td><td headers="hd_h_ml080.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Dose Response biochemical
|
||
assay to measure P97 ATPase inhibition: synthesized
|
||
compounds</td><td headers="hd_h_ml080.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Dose Response Assay</td><td headers="hd_h_ml080.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P97</td><td headers="hd_h_ml080.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Yes</td><td headers="hd_h_ml080.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">10-point, 1:3 dilution
|
||
starting at 50 μM</td></tr><tr><td headers="hd_h_ml080.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1629" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1629</a></td><td headers="hd_h_ml080.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Dose Response biochemical
|
||
assay to measure C522A mutant P97 ATPase inhibition:
|
||
synthesized compounds</td><td headers="hd_h_ml080.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Dose Response Assay</td><td headers="hd_h_ml080.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P97 C522A mutant</td><td headers="hd_h_ml080.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Yes</td><td headers="hd_h_ml080.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">10-point, 1:3 dilution
|
||
starting at 50 μM</td></tr><tr><td headers="hd_h_ml080.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">refer to Summary AID
|
||
(TBD)</td><td headers="hd_h_ml080.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Cell based Ub-GFP
|
||
Turnover</td><td headers="hd_h_ml080.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Dose Response Assay</td><td headers="hd_h_ml080.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">ERAD</td><td headers="hd_h_ml080.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Yes</td><td headers="hd_h_ml080.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6 point, 1:4 dilution
|
||
starting at 10 μM</td></tr><tr><td headers="hd_h_ml080.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1794" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1794</a></td><td headers="hd_h_ml080.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Summary of probe development
|
||
efforts to identify inhibitors of the p97 ATPase</td><td headers="hd_h_ml080.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">N/A</td><td headers="hd_h_ml080.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">N/A</td><td headers="hd_h_ml080.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">N/A</td><td headers="hd_h_ml080.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">N/A</td></tr></tbody></table></div></div></div><div id="ml080.rationale"><h4>ii. Assay Rationale and Description</h4><div id="ml080.t2" class="table"><h3><span class="label">Table 3</span><span class="title">Assay Rationale and Description</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK47346/table/ml080.t2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml080.t2_lrgtbl__"><table class="no_margin"><thead><tr><th id="hd_h_ml080.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">AID</th><th id="hd_h_ml080.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Assay Rationale</th><th id="hd_h_ml080.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Assay Description</th><th id="hd_h_ml080.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Z′</th><th id="hd_h_ml080.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S:B</th></tr></thead><tbody><tr><td headers="hd_h_ml080.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1481" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1481</a></td><td headers="hd_h_ml080.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">The purpose of this assay is
|
||
to measure the ability of compounds to inhibit P97 ATPase
|
||
activity.</td><td headers="hd_h_ml080.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">This biochemical assay employs the
|
||
Kinase-Glo reagent, which contains a luciferase that emits
|
||
luminescence in direct proportion to ATP levels. As
|
||
designed, compounds that inhibit the ATPase activity of p97
|
||
will reduce ATP hydrolysis, thereby increasing the relative
|
||
levels of ATP available for consumption by luciferase,
|
||
resulting in increased well luminescence. Compounds were
|
||
tested in singlicate at a concentration of 8
|
||
μM.</td><td headers="hd_h_ml080.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.8 ±0.03</td><td headers="hd_h_ml080.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1.70±0.1</td></tr><tr><td headers="hd_h_ml080.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1517" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1517</a></td><td headers="hd_h_ml080.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">The purpose of this assay to
|
||
confirm p97 inhibitor activity of compounds identified as
|
||
active in a previous set of experiments (PubChem <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1481" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1481</a>)
|
||
the ability of compounds to inhibit P97 ATPase activity</td><td headers="hd_h_ml080.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Same as <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1481" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1481</a>, except that
|
||
compounds were tested in triplicate.</td><td headers="hd_h_ml080.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.81 ±0.02</td><td headers="hd_h_ml080.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1.73±0.02</td></tr><tr><td headers="hd_h_ml080.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1534" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1534</a></td><td headers="hd_h_ml080.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">The purpose of this assay is
|
||
to determine dose response curves for compounds identified
|
||
as active in a previous set of experiments (PubChem
|
||
<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1481" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1481</a>), and that confirmed activity in PubChem
|
||
<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1517" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1517</a></td><td headers="hd_h_ml080.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Same as <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1481" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1481</a>, except that
|
||
compounds were tested in triplicate using a 10-point, 1:3
|
||
dilution series, starting at a nominal concentration of 50
|
||
µM.</td><td headers="hd_h_ml080.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NA</td><td headers="hd_h_ml080.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NA</td></tr><tr><td headers="hd_h_ml080.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1544" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1544</a></td><td headers="hd_h_ml080.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">The purpose of this assay is
|
||
to determine whether compounds identified as active in
|
||
<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1481" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1481</a> and that confirmed activity in PubChem <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1517" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1517</a> act
|
||
as covalent or non-covalent p97 inhibitors.</td><td headers="hd_h_ml080.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Same as above except that the
|
||
target of the assay is the p97Cys522Ala mutant protein.</td><td headers="hd_h_ml080.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NA</td><td headers="hd_h_ml080.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NA</td></tr><tr><td headers="hd_h_ml080.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1551" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1551</a></td><td headers="hd_h_ml080.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">The purpose of this assay is
|
||
to determine dose response curves for compounds synthesized
|
||
to explore structure activity relationship of
|
||
<a href="https://pubchem.ncbi.nlm.nih.gov/substance/14723044" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-14723044</a>.</td><td headers="hd_h_ml080.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Same as <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1481" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1481</a>, except
|
||
compounds tested were synthesized by Ed Roberts group,
|
||
TSRI.</td><td headers="hd_h_ml080.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NA</td><td headers="hd_h_ml080.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NA</td></tr><tr><td headers="hd_h_ml080.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1629" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1629</a></td><td headers="hd_h_ml080.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">The purpose of this assay is
|
||
to determine dose response curves for compounds synthesized
|
||
to explore structure activity relationship of
|
||
<a href="https://pubchem.ncbi.nlm.nih.gov/substance/14723044" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-14723044</a>.</td><td headers="hd_h_ml080.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Same as above except that the
|
||
target of the assay is the p97Cys522Ala mutant protein.</td><td headers="hd_h_ml080.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NA</td><td headers="hd_h_ml080.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NA</td></tr><tr><td headers="hd_h_ml080.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Ub-GFP Assay (refer to
|
||
Summary AID TBD)</td><td headers="hd_h_ml080.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">The purpose of this assay is
|
||
to determine whether compounds can modulate accumulation of
|
||
the proteasome activity reporter, Ub(G76V)-GFP. The assay
|
||
also serves to identify compounds that are cell-
|
||
permeable.</td><td headers="hd_h_ml080.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">This cell-based assay employs
|
||
HeLa cells that stably express the Ub(G76V)-GFP reporter
|
||
protein to monitor protein accumulation. As designed,
|
||
compounds that inhibit endogenous cellular p97 will lead to
|
||
reporter accumulation and cell fluorescence, resulting in
|
||
increased well fluorescence.</td><td headers="hd_h_ml080.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NA</td><td headers="hd_h_ml080.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NA</td></tr><tr><td headers="hd_h_ml080.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1794" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1794</a></td><td headers="hd_h_ml080.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">The purpose of this AID is to
|
||
summarize probe development efforts for the P97 ATPase</td><td headers="hd_h_ml080.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">N/A</td><td headers="hd_h_ml080.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">N/A</td><td headers="hd_h_ml080.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">N/A</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div id="ml080.tfn2"><p class="no_margin">NA, Not Applicable</p></div></dd></dl></div></div></div><div id="ml080.t3" class="table"><h3><span class="label">Table 4</span><span class="title">Reagents and Source</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK47346/table/ml080.t3/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml080.t3_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml080.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">Assay (AID)</th><th id="hd_h_ml080.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">Reagent (Source)</th></tr></thead><tbody><tr><td headers="hd_h_ml080.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<ul><li class="half_rhythm"><div><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1481" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1481</a></div></li><li class="half_rhythm"><div><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1517" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1517</a></div></li><li class="half_rhythm"><div><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1534" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1534</a></div></li><li class="half_rhythm"><div><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1551" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1551</a></div></li></ul>
|
||
</td><td headers="hd_h_ml080.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Recombinant p97 protein (produced
|
||
in the Deshaies Laboratory)<br />Magnesium Chloride
|
||
(Fisher, part M33-500)<br />1M Tris, pH 8.0 (Invitrogen,
|
||
part T-3038)<br />0.5M EDTA (Invitrogen, part
|
||
15575-025)<br />Dithiothreitol (Fisher, part
|
||
BP172-25)<br />3N Sodium Acetate pH 5.2 (Sigma, part
|
||
S7899)<br />ATP (Sigma, part A7699-1G)<br />Kinase-Glo
|
||
(Promega, part K1214)<br />Methanol (Fisher, part
|
||
A412-4)<br />DMSO (Acros Organics, part
|
||
127790025)<br />1536-well plates (Greiner, part
|
||
789072)<br />384-well plates (Corning, part 3704)</td></tr><tr><td headers="hd_h_ml080.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<ul><li class="half_rhythm"><div>C522A mut DRUN (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1544" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1544</a>)</div></li><li class="half_rhythm"><div>C522A mut DRUN SAR (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1629" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1629</a>)</div></li></ul>
|
||
</td><td headers="hd_h_ml080.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">All as above except replace
|
||
Recombinant p97 protein (produced in the Deshaies
|
||
Laboratory) with mutant p97 C522A protein</td></tr><tr><td headers="hd_h_ml080.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Ub-GFP Assay (refer to
|
||
Summary AID TBD)</td><td headers="hd_h_ml080.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MG132 (Biomol, part
|
||
PI102-0025)<br />PBS ( Invitrogen, part
|
||
10010-049)<br />DMEM (Invitrogen, part
|
||
10313-039)<br />FBS (Atlanta Biological, part
|
||
s115)<br />Penicillin-Streptomycin (Invitrogen, part
|
||
15140-163)<br />Cycloheximide (Calbiochem, part
|
||
239763)<br />96-Well CELLSTAR® Black
|
||
μClear Bottom Plates (ISC Bioexpress, part
|
||
T-3026-16)<br />BD Falcon Standard Tissue Culture Dishes
|
||
100 dia. x 20mm H (Fisher Scientific,
|
||
part08-772E)<br />HeLa cells stably expressing
|
||
Ub-<sub>G76V</sub>-GFP reporter (obtained from Nico
|
||
Dantuma (<a class="bk_pop" href="#ml080.r1">1</a>,<a class="bk_pop" href="#ml080.r2">2</a>).</td></tr></tbody></table></div></div></div><div id="ml080.s5"><h4>iii. Summary of Results</h4><p>This compound represents the first non-covalent, cell active P97 inhibitor
|
||
and will be useful as a lead candidate for the development of P97 specific
|
||
inhibitors</p></div></div><div id="ml080.s7"><h3>b. Probe Optimization</h3><div id="ml080.s8"><h4>i. SAR and Chemistry Strategy</h4><p>The Scripps Chemistry Coordination Committee selected
|
||
CID-14723044 as one of the chemically tractable lead
|
||
compounds. In an initial round of synthesis, 16 compounds were made and
|
||
tested in the <i>in vitro</i> assay. The two active compounds were
|
||
selected for further testing in the Assay Provider’s (Deshaies)
|
||
Lab in the Ub-GFP assay. One of these two compounds were active in the
|
||
biochemical ATPase inhibition. One of these two, CID-25110544, was active in
|
||
an a assay designed to measure p97 cellular-base Ub-GFP turnover
|
||
activity.</p></div></div></div><div id="ml080.s9"><h2 id="_ml080_s9_">3. Probe</h2><div id="ml080.s10"><h3>a. Chemical name</h3><p>4-(4-(2,4-dihydroxyphenyl)thiazol-2-ylamino)-2-trifluoromethyl) benzo-nitrile
|
||
[<a href="/pcsubstance/?term=ML080[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML080</a>]</p></div><div id="ml080.s11"><h3>b. Chemical structure</h3><div id="ml080.fu3" class="figure"><div class="graphic"><img src="/books/NBK47346/bin/ml080fu3.jpg" alt="Image ml080fu3" /></div></div></div><div id="ml080.s12"><h3>c. Structural Verification Information of probe SID</h3><p>LCMS.</p></div><div id="ml080.s13"><h3>d. PubChem CID (corresponding to the SID)</h3><p>CID-25110544</p></div><div id="ml080.s14"><h3>e. Availability from a vendor</h3><p>Not available</p></div><div id="ml080.s15"><h3>f. Mode of action for biological activity of probe</h3><p>The probe compound reduces turnover of ubiquitin-GFP (7.5 µM IC50), and thus
|
||
meets probe criteria.</p></div><div id="ml080.s16"><h3>g. Detailed synthetic pathway for making probe</h3><div id="ml080.fu4" class="figure"><div class="graphic"><img src="/books/NBK47346/bin/ml080fu4.jpg" alt="Image ml080fu4" /></div></div></div><div id="ml080.s17"><h3>h. Summary of probe properties</h3><p>Aqueous solubility, --5.60170850230174; ADMET BBB, Not determined; ADMET BBB
|
||
level, 4; ADMET absorption level, 0; ADMET solubility, −6.273; ADMET
|
||
solubility level, 1</p><div id="ml080.t4" class="table"><h3><span class="label">Table 5</span><span class="title">Probe Properties</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK47346/table/ml080.t4/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml080.t4_lrgtbl__"><table class="no_margin"><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<b>PubChem CID</b>
|
||
</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CID-25110544</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<b>PubChem SID</b>
|
||
</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/56432669" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-56432669</a></td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<b>ML#</b>
|
||
</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="/pcsubstance/?term=ML080[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML080</a></td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>IUPAC Name</b>
|
||
</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">4-[[4-(2,4-dihydroxyphenyl)-1,3-thiazol-2-yl]amino]-2-
|
||
(trifluoromethyl)benzonitrile</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<b>MLS</b>
|
||
</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">None</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">
|
||
<b>MF</b>
|
||
</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">C<sub>17</sub>H<sub>10</sub>F<sub>3</sub>N<sub>3</sub>O<sub>2</sub>S</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<b>MW</b>
|
||
</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">377.3404</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<b>Formal Charge</b>
|
||
</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<b>H Acceptor</b>
|
||
</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">8</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<b>H Donor</b>
|
||
</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<b>Atom Count</b>
|
||
</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">26</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<b>Rotatable Bonds</b>
|
||
</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<b>Rings</b>
|
||
</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<b>Stereoatoms</b>
|
||
</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<b>AlogP</b>
|
||
</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">4.024</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<b>logD</b>
|
||
</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">4.022</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<b>Topological Polar surface area</b>
|
||
</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">89.2</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<b>Aqueous solubility</b>
|
||
<sup><a class="bk_pop" href="#ml080.tfn3">a</a></sup>
|
||
</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">−5.60170850230174</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<b>ADMET BBB</b>
|
||
<sup><a class="bk_pop" href="#ml080.tfn4">b</a></sup>
|
||
</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Not determined</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<b>ADMET BBB level</b>
|
||
<sup><a class="bk_pop" href="#ml080.tfn5">c</a></sup>
|
||
</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">4</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<b>ADMET absorption level</b>
|
||
<sup><a class="bk_pop" href="#ml080.tfn6">d</a></sup>
|
||
</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<b>ADMET solubility</b>
|
||
<sup><a class="bk_pop" href="#ml080.tfn7">e</a></sup>
|
||
</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">−6.273</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<b>ADMETT solubility level</b>
|
||
<sup>f</sup>
|
||
</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">
|
||
<b>Vendor</b>
|
||
</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">In House synthesis (TSRI)</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<b>Vendor Catalog Number</b>
|
||
</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">None</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>a</dt><dd><div id="ml080.tfn3"><p class="no_margin">Aqueous solubility is expressed as logS, where S is solubility in
|
||
mol/L. The method used is the multiple linear regression model based
|
||
on Electrotopological State indices published in (<a class="bk_pop" href="#ml080.r2">2</a>)(<a class="bk_pop" href="#ml080.r7">7</a>).</p></div></dd><dt>b</dt><dd><div id="ml080.tfn4"><p class="no_margin">ADMET_BBB: Log of Brain/Blood partition coefficient (LogBB). See
|
||
(<a class="bk_pop" href="#ml080.r4">4</a>) for details on
|
||
this method.</p></div></dd><dt>c</dt><dd><div id="ml080.tfn5"><p class="no_margin">ADMET_BBB_Level: Ranking of the LogBB values into one of the
|
||
following levels (see (<a class="bk_pop" href="#ml080.r4">4</a>, <a class="bk_pop" href="#ml080.r5">5</a>) for
|
||
details): 0: Very High 1: High 2: Medium 3: Low 4: Undefined
|
||
(molecule is outside the confidence area of the regression
|
||
model).</p></div></dd><dt>d</dt><dd><div id="ml080.tfn6"><p class="no_margin">ADMET Passive Intestinal Absorption properties. A ranking of the
|
||
molecule into one of the following levels (see (<a class="bk_pop" href="#ml080.r4">4</a>, <a class="bk_pop" href="#ml080.r5">5</a>) for details): 0: Good 1: Moderate 2: Poor 3: Very
|
||
Poor</p></div></dd><dt>e</dt><dd><div id="ml080.tfn7"><p class="no_margin">ADMET_Solubility: Log of the water solubility at 25 degrees, LogSw,
|
||
in mol/L. See (<a class="bk_pop" href="#ml080.r6">6</a>) for
|
||
more information.</p></div></dd></dl></div></div></div></div></div><div id="ml080.s18"><h2 id="_ml080_s18_">4. Appendices</h2><div id="ml080.tu2" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK47346/table/ml080.tu2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml080.tu2_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_ml080.tu2_1_1_1_1" colspan="8" rowspan="1" style="text-align:center;vertical-align:bottom;">
|
||
<div class="graphic"><img src="/books/NBK47346/bin/ml080fu5.jpg" alt="Image ml080fu5.jpg" /></div>
|
||
</th></tr><tr><th headers="hd_h_ml080.tu2_1_1_1_1" id="hd_h_ml080.tu2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">R1</th><th headers="hd_h_ml080.tu2_1_1_1_1" id="hd_h_ml080.tu2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">R2</th><th headers="hd_h_ml080.tu2_1_1_1_1" id="hd_h_ml080.tu2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLSMR SID</th><th headers="hd_h_ml080.tu2_1_1_1_1" id="hd_h_ml080.tu2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLSMR CID</th><th headers="hd_h_ml080.tu2_1_1_1_1" id="hd_h_ml080.tu2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS</th><th headers="hd_h_ml080.tu2_1_1_1_1" id="hd_h_ml080.tu2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Vendor</th><th headers="hd_h_ml080.tu2_1_1_1_1" id="hd_h_ml080.tu2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IC<sub>50</sub> (M) p97 activity</th><th headers="hd_h_ml080.tu2_1_1_1_1" id="hd_h_ml080.tu2_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IC<sub>50</sub> (M) Ub-GFP
|
||
turnover</th></tr></thead><tbody><tr><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
|
||
<div class="graphic"><img src="/books/NBK47346/bin/ml080fu6.jpg" alt="Image ml080fu6.jpg" /></div>
|
||
</td><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
|
||
<div class="graphic"><img src="/books/NBK47346/bin/ml080fu7.jpg" alt="Image ml080fu7.jpg" /></div>
|
||
</td><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">56432228</td><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">25110136</td><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">None</td><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Roberts Lab, TSRI</td><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4.7e-6</td><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NA</td></tr><tr><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
|
||
<div class="graphic"><img src="/books/NBK47346/bin/ml080fu8.jpg" alt="Image ml080fu8.jpg" /></div>
|
||
</td><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
|
||
<div class="graphic"><img src="/books/NBK47346/bin/ml080fu9.jpg" alt="Image ml080fu9.jpg" /></div>
|
||
</td><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">56432230</td><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">25110138</td><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">None</td><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Roberts Lab, TSRI</td><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>50e-6</td><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">ND</td></tr><tr><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
|
||
<div class="graphic"><img src="/books/NBK47346/bin/ml080fu10.jpg" alt="Image ml080fu10.jpg" /></div>
|
||
</td><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
|
||
<div class="graphic"><img src="/books/NBK47346/bin/ml080fu11.jpg" alt="Image ml080fu11.jpg" /></div>
|
||
</td><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">56432232</td><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">25110139</td><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">None</td><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Roberts Lab, TSRI</td><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>50e-6</td><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">ND</td></tr><tr><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
|
||
<div class="graphic"><img src="/books/NBK47346/bin/ml080fu12.jpg" alt="Image ml080fu12.jpg" /></div>
|
||
</td><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
|
||
<div class="graphic"><img src="/books/NBK47346/bin/ml080fu13.jpg" alt="Image ml080fu13.jpg" /></div>
|
||
</td><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">56432234</td><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">25110140</td><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">None</td><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Roberts Lab, TSRI</td><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>50e-6</td><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">ND</td></tr><tr><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
|
||
<div class="graphic"><img src="/books/NBK47346/bin/ml080fu14.jpg" alt="Image ml080fu14.jpg" /></div>
|
||
</td><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
|
||
<div class="graphic"><img src="/books/NBK47346/bin/ml080fu15.jpg" alt="Image ml080fu15.jpg" /></div>
|
||
</td><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">56432236</td><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">25110141</td><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">None</td><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Roberts Lab, TSRI</td><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>50e-6</td><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">ND</td></tr><tr><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
|
||
<div class="graphic"><img src="/books/NBK47346/bin/ml080fu16.jpg" alt="Image ml080fu16.jpg" /></div>
|
||
</td><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
|
||
<div class="graphic"><img src="/books/NBK47346/bin/ml080fu17.jpg" alt="Image ml080fu17.jpg" /></div>
|
||
</td><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">56432238</td><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">25110143</td><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">None</td><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Roberts Lab, TSRI</td><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>50e-6</td><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">ND</td></tr><tr><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
|
||
<div class="graphic"><img src="/books/NBK47346/bin/ml080fu18.jpg" alt="Image ml080fu18.jpg" /></div>
|
||
</td><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
|
||
<div class="graphic"><img src="/books/NBK47346/bin/ml080fu19.jpg" alt="Image ml080fu19.jpg" /></div>
|
||
</td><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">56432668</td><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">25110543</td><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">None</td><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Roberts Lab, TSRI</td><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3.7e-6</td><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">7e-6</td></tr><tr><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
|
||
<div class="graphic"><img src="/books/NBK47346/bin/ml080fu20.jpg" alt="Image ml080fu20.jpg" /></div>
|
||
</td><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
|
||
<div class="graphic"><img src="/books/NBK47346/bin/ml080fu21.jpg" alt="Image ml080fu21.jpg" /></div>
|
||
</td><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">56432376</td><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">25110268</td><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">None</td><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Roberts Lab, TSRI</td><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>50e-6</td><td headers="hd_h_ml080.tu2_1_1_1_1 hd_h_ml080.tu2_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">ND</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div id="ml080.tfn8"><p class="no_margin">NA: Not Active, ND Not Determined</p></div></dd></dl></div></div></div><div id="ml080.app1"><h3>Appendix 1. Endoplasmic reticulum-associated degradation (ERAD) Assay
|
||
(Ub-<sub>G76V</sub>-GFP/HeLa Titration Assay)</h3><p>In order to determine whether the identified p97 inhibitors were cell permeable
|
||
and could inhibit endogenous p97 in vivo, ERAD assays were performed for
|
||
selected compounds. Ub-<sub>G76V</sub>-GFP/HeLa cells were treated with MG132 (2
|
||
μM) for 1h and washed with PBS three times. DMEM containing
|
||
cycloheximide (50 μg/mL) and test compounds (0 ~ 10 μM)
|
||
was added to wells. 8 of 96 well plates were prepared and one of the plates was
|
||
imaged at 25, 50, 70, 100, 110,125, 145, or 170 minutes after washing with PBS 3
|
||
times.</p><div id="ml080.fu5" class="figure"><div class="graphic"><img src="/books/NBK47346/bin/ml080fu22.jpg" alt="Image ml080fu22" /></div></div><div id="ml080.fu6" class="figure"><div class="graphic"><img src="/books/NBK47346/bin/ml080fu23.jpg" alt="Image ml080fu23" /></div></div><div id="ml080.fu7" class="figure"><div class="graphic"><img src="/books/NBK47346/bin/ml080fu24.jpg" alt="Image ml080fu24" /></div></div><div id="ml080.fu8" class="figure"><div class="graphic"><img src="/books/NBK47346/bin/ml080fu25.jpg" alt="Image ml080fu25" /></div></div></div></div><div id="ml080.bib"><h2 id="_ml080_bib_">5. Bibliography</h2><dl class="temp-labeled-list"><dt>1.</dt><dd><div class="bk_ref" id="ml080.r1">Raasi S, Wolf DH. Ubiquitin receptors and ERAD: a network of pathways to the
|
||
proteasome. <span><span class="ref-journal">Seminars in cell & developmental biology. </span>2007;<span class="ref-vol">18</span>:780–791.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17942349" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17942349</span></a>]</div></dd><dt>2.</dt><dd><div class="bk_ref" id="ml080.r2">Halawani D, Latterich M. p97: The cell’s molecular
|
||
purgatory? <span><span class="ref-journal">Molecular cell. </span>2006;<span class="ref-vol">22</span>:713–717.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16793541" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16793541</span></a>]</div></dd><dt>3.</dt><dd><div class="bk_ref" id="ml080.r3">Wang Q, Li L, Ye Y. Inhibition of p97-dependent protein degradation by
|
||
Eeyarestatin I. <span><span class="ref-journal">The Journal of biological chemistry. </span>2008;<span class="ref-vol">283</span>:7445–7454.</span> [<a href="/pmc/articles/PMC2276333/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2276333</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18199748" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18199748</span></a>]</div></dd><dt>4.</dt><dd><div class="bk_ref" id="ml080.r4">Mizuno Y, Hori S, Kakizuka A, Okamoto K. Vacuole-creating protein in neurodegenerative diseases in
|
||
humans. <span><span class="ref-journal">Neuroscience letters. </span>2003;<span class="ref-vol">343</span>:77–80.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12759168" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12759168</span></a>]</div></dd><dt>5.</dt><dd><div class="bk_ref" id="ml080.r5">Watts GD, Wymer J, Kovach MJ, Mehta SG, Mumm S, Darvish D, Pestronk A, Whyte MP, Kimonis VE. Inclusion body myopathy associated with Paget disease of bone
|
||
and frontotemporal dementia is caused by mutant valosin-containing
|
||
protein. <span><span class="ref-journal">Nature genetics. </span>2004;<span class="ref-vol">36</span>:377–381.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15034582" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15034582</span></a>]</div></dd><dt>6.</dt><dd><div class="bk_ref" id="ml080.r6">Weihl CC, Dalal S, Pestronk A, Hanson PI. Inclusion body myopathy-associated mutations in p97/VCP
|
||
impair endoplasmic reticulum-associated degradation. <span><span class="ref-journal">Human molecular genetics. </span>2006;<span class="ref-vol">15</span>:189–199.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16321991" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16321991</span></a>]</div></dd><dt>7.</dt><dd><div class="bk_ref" id="ml080.r7">Tetko IV, Tanchuk VY, Kasheva TN, Villa AE. Estimation of aqueous solubility of chemical compounds using
|
||
E-state indices. <span><span class="ref-journal">J Chem Inf Comput Sci. </span>2001;<span class="ref-vol">41</span>:1488–1493.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11749573" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11749573</span></a>]</div></dd><dt>8.</dt><dd><div class="bk_ref" id="ml080.r8">Ishigaki S, Hishikawa N, Niwa J, Iemura S, Natsume T, Hori S, Kakizuka A, Tanaka K, Sobue G. Physical and functional interaction between Dorfin and
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Valosin-containing protein that are colocalized in ubiquitylated
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inclusions in neurodegenerative disorders. <span><span class="ref-journal">J Biol Chem. </span>2004 2004 Dec 3;<span class="ref-vol">279</span>(49:):51376–85.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15456787" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15456787</span></a>]</div></dd><dt>9.</dt><dd><div class="bk_ref" id="ml080.r9">Hirabayashi M, Inoue K, Tanaka K, Nakadate K, Ohsawa Y, Kamei Y, Popiel AH, Sinohara A, Iwamatsu A, Kimura Y, Uchiyama Y, Hori S, Kakizuka A. VCP/p97 in abnormal protein aggregates, cytoplasmic vacuoles,
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and cell death, phenotypes relevant to neurodegeneration. <span><span class="ref-journal">Cell Death Differ. </span>2001;<span class="ref-vol">8</span>:977–984.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11598795" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11598795</span></a>]</div></dd></dl></div><div id="bk_toc_contnr"></div></div></div>
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<div class="post-content"><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright Notice</a></div><div class="small"><span class="label">Bookshelf ID: NBK47346</span><span class="label">PMID: <a href="https://pubmed.ncbi.nlm.nih.gov/21433362" title="PubMed record of this page" ref="pagearea=meta&targetsite=entrez&targetcat=link&targettype=pubmed">21433362</a></span></div><div style="margin-top:2em" class="bk_noprnt"><a class="bk_cntns" href="/books/n/mlprobe/">Contents</a><div class="pagination bk_noprnt"><a class="active page_link prev" href="/books/n/mlprobe/ml081/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/mlprobe/ml079/" title="Next page in this title">Next ></a></div></div></div></div>
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<div xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Views</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="PDF_download" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="/books/NBK47346/?report=reader">PubReader</a></li><li><a href="/books/NBK47346/?report=printable">Print View</a></li><li><a data-jig="ncbidialog" href="#_ncbi_dlg_citbx_NBK47346" data-jigconfig="width:400,modal:true">Cite this Page</a><div id="_ncbi_dlg_citbx_NBK47346" style="display:none" title="Cite this Page"><div class="bk_tt">Brown SJ, Chou TF, Deshaies R, et al. Probe Report for P97/cdc48 Inhibitors. 2009 Mar 6 [Updated 2010 Aug 6]. In: Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010-. <span class="bk_cite_avail"></span></div></div></li><li><a href="/books/NBK47346/pdf/Bookshelf_NBK47346.pdf">PDF version of this page</a> (143K)</li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>In this Page</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="page-toc" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="#ml080.s1" ref="log$=inpage&link_id=inpage">Probe Structure & Characteristics</a></li><li><a href="#ml080.s2" ref="log$=inpage&link_id=inpage">Recommendations for the scientific use of this probe</a></li><li><a href="#ml080.s3" ref="log$=inpage&link_id=inpage">Scientific Rationale for Project</a></li><li><a href="#ml080.s4" ref="log$=inpage&link_id=inpage">Project Description</a></li><li><a href="#ml080.s9" ref="log$=inpage&link_id=inpage">Probe</a></li><li><a href="#ml080.s18" ref="log$=inpage&link_id=inpage">Appendices</a></li><li><a href="#ml080.bib" ref="log$=inpage&link_id=inpage">Bibliography</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Related information</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="discovery_db_links" id="Shutter"></a></div><div class="portlet_content"><ul><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pmc&DbFrom=books&Cmd=Link&LinkName=books_pmc_refs&IdsFromResult=2359038" ref="log$=recordlinks">PMC</a><div class="brieflinkpop offscreen_noflow">PubMed Central citations</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pcassay&DbFrom=books&Cmd=Link&LinkName=books_pcassay_probe&IdsFromResult=2359038" ref="log$=recordlinks">PubChem BioAssay for Chemical Probe</a><div class="brieflinkpop offscreen_noflow">PubChem BioAssay records reporting screening data for the development of the chemical probe(s) described in this book chapter</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pcsubstance&DbFrom=books&Cmd=Link&LinkName=books_pcsubstance&IdsFromResult=2359038" ref="log$=recordlinks">PubChem Substance</a><div class="brieflinkpop offscreen_noflow">Related PubChem Substances</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pubmed&DbFrom=books&Cmd=Link&LinkName=books_pubmed_refs&IdsFromResult=2359038" ref="log$=recordlinks">PubMed</a><div class="brieflinkpop offscreen_noflow">Links to PubMed</div></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Similar articles in PubMed</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="PBooksDiscovery_RA" id="Shutter"></a></div><div class="portlet_content"><ul><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/17942349" ref="ordinalpos=1&linkpos=1&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Ubiquitin receptors and ERAD: a network of pathways to the proteasome.</a><span class="source">[Semin Cell Dev Biol. 2007]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Ubiquitin receptors and ERAD: a network of pathways to the proteasome.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Raasi S, Wolf DH. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">Semin Cell Dev Biol. 2007 Dec; 18(6):780-91. 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