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<meta name="ncbi_db" content="books" /><meta name="ncbi_pdid" content="book-part" /><meta name="ncbi_acc" content="NBK189923" /><meta name="ncbi_domain" content="mlprobe" /><meta name="ncbi_report" content="record" /><meta name="ncbi_type" content="fulltext" /><meta name="ncbi_objectid" content="" /><meta name="ncbi_pcid" content="/NBK189923/" /><meta name="ncbi_pagename" content="Selective inhibitors of FAS-TE - Probe Reports from the NIH Molecular Libraries Program - NCBI Bookshelf" /><meta name="ncbi_bookparttype" content="chapter" /><meta name="ncbi_app" content="bookshelf" />
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<title>Selective inhibitors of FAS-TE - Probe Reports from the NIH Molecular Libraries Program - NCBI Bookshelf</title>
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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="Selective inhibitors of FAS-TE" /><meta name="citation_publisher" content="National Center for Biotechnology Information (US)" /><meta name="citation_date" content="2014/01/13" /><meta name="citation_author" content="Robert Ardecky" /><meta name="citation_author" content="Michael P. Hedrick" /><meta name="citation_author" content="Palak Gosalia" /><meta name="citation_author" content="Fusayo Yamamoto" /><meta name="citation_author" content="Monika Milewski" /><meta name="citation_author" content="Nikki Barron" /><meta name="citation_author" content="Qing Sun" /><meta name="citation_author" content="Jiwen Zhou" /><meta name="citation_author" content="Santhi Ganji" /><meta name="citation_author" content="Alka Mehta" /><meta name="citation_author" content="Elliot Sugarman" /><meta name="citation_author" content="Kevin Nguyen" /><meta name="citation_author" content="Stefan Vasile" /><meta name="citation_author" content="Eigo Suyama" /><meta name="citation_author" content="Peter Teriete" /><meta name="citation_author" content="Douglas Sheffler" /><meta name="citation_author" content="Pooi San Lee" /><meta name="citation_author" content="Margrith Mattmann" /><meta name="citation_author" content="Jessica De Ingeniis" /><meta name="citation_author" content="Derek Stonich" /><meta name="citation_author" content="Arianna Mangravita-Novo" /><meta name="citation_author" content="Sumeet Salaniwal" /><meta name="citation_author" content="Paul Kung" /><meta name="citation_author" content="Jena Diwan" /><meta name="citation_author" content="Layton H. Smith" /><meta name="citation_author" content="Eduard Sergienko" /><meta name="citation_author" content="Thomas D.Y. Chung" /><meta name="citation_author" content="Anthony B. Pinkerton" /><meta name="citation_author" content="Nicholas D. P. Cosford" /><meta name="citation_author" content="Jeffrey W. Smith" /><meta name="citation_pmid" content="24624464" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK189923/" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="Selective inhibitors of FAS-TE" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="National Center for Biotechnology Information (US)" /><meta name="DC.Contributor" content="Robert Ardecky" /><meta name="DC.Contributor" content="Michael P. Hedrick" /><meta name="DC.Contributor" content="Palak Gosalia" /><meta name="DC.Contributor" content="Fusayo Yamamoto" /><meta name="DC.Contributor" content="Monika Milewski" /><meta name="DC.Contributor" content="Nikki Barron" /><meta name="DC.Contributor" content="Qing Sun" /><meta name="DC.Contributor" content="Jiwen Zhou" /><meta name="DC.Contributor" content="Santhi Ganji" /><meta name="DC.Contributor" content="Alka Mehta" /><meta name="DC.Contributor" content="Elliot Sugarman" /><meta name="DC.Contributor" content="Kevin Nguyen" /><meta name="DC.Contributor" content="Stefan Vasile" /><meta name="DC.Contributor" content="Eigo Suyama" /><meta name="DC.Contributor" content="Peter Teriete" /><meta name="DC.Contributor" content="Douglas Sheffler" /><meta name="DC.Contributor" content="Pooi San Lee" /><meta name="DC.Contributor" content="Margrith Mattmann" /><meta name="DC.Contributor" content="Jessica De Ingeniis" /><meta name="DC.Contributor" content="Derek Stonich" /><meta name="DC.Contributor" content="Arianna Mangravita-Novo" /><meta name="DC.Contributor" content="Sumeet Salaniwal" /><meta name="DC.Contributor" content="Paul Kung" /><meta name="DC.Contributor" content="Jena Diwan" /><meta name="DC.Contributor" content="Layton H. Smith" /><meta name="DC.Contributor" content="Eduard Sergienko" /><meta name="DC.Contributor" content="Thomas D.Y. Chung" /><meta name="DC.Contributor" content="Anthony B. Pinkerton" /><meta name="DC.Contributor" content="Nicholas D. P. Cosford" /><meta name="DC.Contributor" content="Jeffrey W. Smith" /><meta name="DC.Date" content="2014/01/13" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK189923/" /><meta name="description" content="Fatty acid synthase (FAS) is the single human enzyme that can convert dietary carbohydrate to fat. The FAS protein contains six enzymatic domains and an acyl-carrier protein (ACP). The final enzymatic pocket is a thioesterase (TE), which liberates the final product (palmitate) from its link to the ACP. Notably, FAS has only marginal importance in adults because dietary fat provides for normal physiology. However, a link between FAS and cancer was discovered in 1994 when Frank Kuhajda found that the OA-519 antigen, a marker for poor prognosis in breast and prostate cancer, is actually fatty acid synthase. A number of subsequent immunohistochemical analyses showed that increased expression of FAS is a hallmark of all major cancers including those of the prostate, the breast, the colon, and the ovaries. Therefore, FAS represents a compelling target for anticancer drug discovery. To our knowledge, no thioesterase (TE) has ever been targeted for drug development, including the TE domain of FAS." /><meta name="og:title" content="Selective inhibitors of FAS-TE" /><meta name="og:type" content="book" /><meta name="og:description" content="Fatty acid synthase (FAS) is the single human enzyme that can convert dietary carbohydrate to fat. The FAS protein contains six enzymatic domains and an acyl-carrier protein (ACP). The final enzymatic pocket is a thioesterase (TE), which liberates the final product (palmitate) from its link to the ACP. Notably, FAS has only marginal importance in adults because dietary fat provides for normal physiology. However, a link between FAS and cancer was discovered in 1994 when Frank Kuhajda found that the OA-519 antigen, a marker for poor prognosis in breast and prostate cancer, is actually fatty acid synthase. A number of subsequent immunohistochemical analyses showed that increased expression of FAS is a hallmark of all major cancers including those of the prostate, the breast, the colon, and the ovaries. Therefore, FAS represents a compelling target for anticancer drug discovery. To our knowledge, no thioesterase (TE) has ever been targeted for drug development, including the TE domain of FAS." /><meta name="og:url" content="https://www.ncbi.nlm.nih.gov/books/NBK189923/" /><meta name="og:site_name" content="NCBI Bookshelf" /><meta name="og:image" content="https://www.ncbi.nlm.nih.gov/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-mlprobe-lrg.png" /><meta name="twitter:card" content="summary" /><meta name="twitter:site" content="@ncbibooks" /><meta name="bk-non-canon-loc" content="/books/n/mlprobe/ml356/" /><link rel="canonical" href="https://www.ncbi.nlm.nih.gov/books/NBK189923/" /><link rel="stylesheet" href="/corehtml/pmc/css/figpopup.css" type="text/css" media="screen" /><link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css/books.min.css" type="text/css" /><link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css/books_print.min.css" type="text/css" media="print" /><style type="text/css">p a.figpopup{display:inline !important} .bk_tt {font-family: monospace} .first-line-outdent .bk_ref {display: inline} .body-content h2, .body-content .h2 {border-bottom: 1px solid #97B0C8} .body-content h2.inline {border-bottom: none} a.page-toc-label , .jig-ncbismoothscroll a {text-decoration:none;border:0 !important} .temp-labeled-list .graphic {display:inline-block !important} .temp-labeled-list img{width:100%}</style><script type="text/javascript" src="/corehtml/pmc/js/jquery.hoverIntent.min.js"> </script><script type="text/javascript" src="/corehtml/pmc/js/common.min.js?_=3.18"> </script><script type="text/javascript" src="/corehtml/pmc/js/large-obj-scrollbars.min.js"> </script><script type="text/javascript">window.name="mainwindow";</script><script type="text/javascript" src="/corehtml/pmc/js/bookshelf/2.26/book-toc.min.js"> </script><script type="text/javascript" src="/corehtml/pmc/js/bookshelf/2.26/books.min.js"> </script><meta name="book-collection" content="NONE" />
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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="#__NBK189923_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK189923_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/ml358/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/mlprobe/ml355/" 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="_NBK189923_"><span class="title" itemprop="name">Selective inhibitors of FAS-TE</span></h1><p class="contrib-group"><span itemprop="author">Robert Ardecky</span>, <span itemprop="author">Michael P. Hedrick</span>, <span itemprop="author">Palak Gosalia</span>, <span itemprop="author">Fusayo Yamamoto</span>, <span itemprop="author">Monika Milewski</span>, <span itemprop="author">Nikki Barron</span>, <span itemprop="author">Qing Sun</span>, <span itemprop="author">Jiwen Zhou</span>, <span itemprop="author">Santhi Ganji</span>, <span itemprop="author">Alka Mehta</span>, <span itemprop="author">Elliot Sugarman</span>, <span itemprop="author">Kevin Nguyen</span>, <span itemprop="author">Stefan Vasile</span>, <span itemprop="author">Eigo Suyama</span>, <span itemprop="author">Peter Teriete</span>, <span itemprop="author">Douglas Sheffler</span>, <span itemprop="author">Pooi San Lee</span>, <span itemprop="author">Margrith Mattmann</span>, <span itemprop="author">Jessica De Ingeniis</span>, <span itemprop="author">Derek Stonich</span>, <span itemprop="author">Arianna Mangravita-Novo</span>, <span itemprop="author">Sumeet Salaniwal</span>, <span itemprop="author">Paul Kung</span>, <span itemprop="author">Jena Diwan</span>, <span itemprop="author">Layton H. Smith</span>, <span itemprop="author">Eduard Sergienko</span>, <span itemprop="author">Thomas D.Y. Chung</span>, <span itemprop="author">Anthony B. Pinkerton</span>, <span itemprop="author">Nicholas D. P. Cosford</span>, and <span itemprop="author">Jeffrey W. Smith</span>.</p><a data-jig="ncbitoggler" href="#__NBK189923_ai__" style="border:0;text-decoration:none">Author Information and Affiliations</a><div style="display:none" class="ui-widget" id="__NBK189923_ai__"><p class="contrib-group"><h4>Authors</h4><span itemprop="author">Robert Ardecky</span>,<sup>1</sup> <span itemprop="author">Michael P. Hedrick</span>,<sup>1</sup> <span itemprop="author">Palak Gosalia</span>,<sup>1</sup> <span itemprop="author">Fusayo Yamamoto</span>,<sup>1</sup> <span itemprop="author">Monika Milewski</span>,<sup>1</sup> <span itemprop="author">Nikki Barron</span>,<sup>1</sup> <span itemprop="author">Qing Sun</span>,<sup>1</sup> <span itemprop="author">Jiwen Zhou</span>,<sup>1</sup> <span itemprop="author">Santhi Ganji</span>,<sup>1</sup> <span itemprop="author">Alka Mehta</span>,<sup>2</sup> <span itemprop="author">Elliot Sugarman</span>,<sup>2</sup> <span itemprop="author">Kevin Nguyen</span>,<sup>2</sup> <span itemprop="author">Stefan Vasile</span>,<sup>2</sup> <span itemprop="author">Eigo Suyama</span>,<sup>2</sup> <span itemprop="author">Peter Teriete</span>,<sup>3</sup> <span itemprop="author">Douglas Sheffler</span>,<sup>3</sup> <span itemprop="author">Pooi San Lee</span>,<sup>3</sup> <span itemprop="author">Margrith Mattmann</span>,<sup>3</sup> <span itemprop="author">Jessica De Ingeniis</span>,<sup>3</sup> <span itemprop="author">Derek Stonich</span>,<sup>1</sup> <span itemprop="author">Arianna Mangravita-Novo</span>,<sup>2</sup> <span itemprop="author">Sumeet Salaniwal</span>,<sup>1</sup> <span itemprop="author">Paul Kung</span>,<sup>1</sup> <span itemprop="author">Jena Diwan</span>,<sup>1</sup> <span itemprop="author">Layton H. Smith</span>,<sup>2</sup> <span itemprop="author">Eduard Sergienko</span>,<sup>1</sup> <span itemprop="author">Thomas D.Y. Chung</span>,<sup>1</sup> <span itemprop="author">Anthony B. Pinkerton</span>,<sup>1</sup> <span itemprop="author">Nicholas D. P. Cosford</span>,<sup>3</sup> and <span itemprop="author">Jeffrey W. Smith</span><sup>3</sup>.<sup><img src="/corehtml/pmc/pmcgifs/corrauth.gif" alt="corresponding author" /></sup></p><h4>Affiliations</h4><div class="affiliation"><sup>1</sup>
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Sanford-Burnham Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA</div><div class="affiliation"><sup>2</sup>
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Sanford-Burnham Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, Orlando, Florida 32827, USA</div><div class="affiliation"><sup>3</sup>
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NCI Designated Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, California 92037</div><div class="affiliation"><sup><img src="/corehtml/pmc/pmcgifs/corrauth.gif" alt="corresponding author" /></sup>Corresponding author: Anthony B. Pinkerton, Ph.D.
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<span class="before-email-separator"></span><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="gro.mahnrubdrofnas@notreknipa" class="oemail">gro.mahnrubdrofnas@notreknipa</a></div></div><p class="small">Received: <span itemprop="datePublished">April 12, 2013</span>; Last Update: <span itemprop="dateModified">January 13, 2014</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>Fatty acid synthase (FAS) is the single human enzyme that can convert dietary carbohydrate to fat. The FAS protein contains six enzymatic domains and an acyl-carrier protein (ACP). The final enzymatic pocket is a thioesterase (TE), which liberates the final product (palmitate) from its link to the ACP. Notably, FAS has only marginal importance in adults because dietary fat provides for normal physiology. However, a link between FAS and cancer was discovered in 1994 when Frank Kuhajda found that the OA-519 antigen, a marker for poor prognosis in breast and prostate cancer, is actually fatty acid synthase. A number of subsequent immunohistochemical analyses showed that <i>increased expression of FAS is a hallmark of all major cancers</i> including those of the prostate, the breast, the colon, and the ovaries. Therefore, FAS represents a compelling target for anticancer drug discovery. To our knowledge, no thioesterase (TE) has ever been targeted for drug development, including the TE domain of FAS.</p><p>This report describes the discovery of a series of aminothiazoles as selective FAS-TE inhibitors. <a href="/pcsubstance/?term=ML356[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML356</a>, the lead compound from this series, is potent (IC<sub>50</sub> = 0.334 μM) and selective inhibitor of FAS-TE. The compounds are selective for FAS over a number of other human thioesterases expressed in tumor cells, and selective for the thioesterase domain of FAS over its most closely related human homolog, ACOT4. <a href="/pcsubstance/?term=ML356[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML356</a> also blocks the biosynthesis of palmitate (the end product of FAS) in cells.</p></div><div class="h2"></div><p><b>Assigned Assay Grant #:</b> DA032474-01 (derived from 1 R01 CA140427-01A1 Cycle 18 - Fast Track)</p><p><b>Screening Center Name & PI:</b> Sanford-Burnham Medical Research Institute & John C. Reed, M.D., Ph.D.</p><p><b>Chemistry Center Name & PI:</b> Sanford-Burnham Medical Research Institute & John C. Reed, M.D., Ph.D.</p><p><b>Assay Submitter & Institution:</b> Jeffrey Smith, Ph.D., Sanford-Burnham Medical Research Institute</p><p><b>PubChem Summary Bioassay Identifier (AID):</b>
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<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/602265" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">602265</a></p><div id="ml356.s1"><h2 id="_ml356_s1_">Probe Structure & Characteristics</h2><p>This Center Probe Report describes <a href="/pcsubstance/?term=ML356[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML356</a>, a selective inhibitor of FAS-TE. <a href="/pcsubstance/?term=ML356[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML356</a> has a central aminothiazole core. The chemical structure and data summary are shown in <a class="figpopup" href="/books/NBK189923/table/ml356.t1/?report=objectonly" target="object" rid-figpopup="figml356t1" rid-ob="figobml356t1">Table 1</a>.</p><div id="ml356.f1" class="figure"><div class="graphic"><img src="/books/NBK189923/bin/ml356f1.jpg" alt="Image ml356f1" /></div></div><div id="ml356.t1" class="table"><h3><span class="label">Table 1</span><span class="title">Summary of Probe ML356 Characteristics</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK189923/table/ml356.t1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml356.t1_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml356.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CID/ML#</th><th id="hd_h_ml356.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Target Name</th><th id="hd_h_ml356.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">IC50/EC50 (nM)<br />[SID, AID]</th></tr></thead><tbody><tr><td headers="hd_h_ml356.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>CID 70680643</b><br /><b><a href="/pcsubstance/?term=ML356[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML356</a></b></td><td headers="hd_h_ml356.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">FAS-TE Inhibitor<br />Fatty Acid Synthase (Thioester domain)</td><td headers="hd_h_ml356.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">334 ± 0.03 (n=4)<br /><a href="https://pubchem.ncbi.nlm.nih.gov/substance/160658425" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 160658425</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/652164" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 652164</a></td></tr></tbody></table></div></div></div><div id="ml356.s2"><h2 id="_ml356_s2_">1. Recommendations for Scientific Use of the Probe</h2><p>The FAS protein contains six enzymatic domains and an acyl-carrier protein (ACP). The final enzymatic pocket is a thioesterase, which liberates the final product (palmitate) from its link to the ACP. It is the thioesterase domain of FAS, which we plan to target here. To our knowledge, no thioesterase (TE) has ever been targeted for drug development. Consequently, the unique enzymatic target and the new chemical entities that will be developed are one novel aspect of the study. Another novel aspect of the study is our intent to identify selective FAS inhibitors, by counter screening against other thioesterases.</p><p>This study will focus on developing drug-like inhibitors/probes against FAS, an enzyme that is essential for growth of solid tumors. Notably, FAS has only marginal importance in adults because dietary fat provides for normal physiology. The link between FAS and cancer was discovered in 1994 when Frank Kuhajda found that the OA-519 antigen, a marker for poor prognosis in breast and prostate cancer [<a class="bk_pop" href="#ml356.r1">1</a>], is actually fatty acid synthase [<a class="bk_pop" href="#ml356.r2">2</a>]. A number of subsequent immunohistochemical analyses showed that <i>increased expression of FAS is a hallmark of all major cancers</i> (for review see [<a class="bk_pop" href="#ml356.r3">3</a>]), including those of the prostate [<a class="bk_pop" href="#ml356.r4">4</a>-<a class="bk_pop" href="#ml356.r6">6</a>], the breast [<a class="bk_pop" href="#ml356.r7">7</a>,<a class="bk_pop" href="#ml356.r8">8</a>], the colon [<a class="bk_pop" href="#ml356.r9">9</a>,<a class="bk_pop" href="#ml356.r10">10</a>], and the ovaries [<a class="bk_pop" href="#ml356.r11">11</a>,<a class="bk_pop" href="#ml356.r12">12</a>].</p><p>Perhaps more significantly, <i>increased expression of FAS in tumors is usually linked with poor prognosis</i>. FAS is an indicator of poor prognosis in cancers of the prostate [<a class="bk_pop" href="#ml356.r13">13</a>], ovaries [<a class="bk_pop" href="#ml356.r11">11</a>], and colon [<a class="bk_pop" href="#ml356.r14">14</a>]. In breast cancer, FAS is a predictor of disease recurrence [<a class="bk_pop" href="#ml356.r8">8</a>], whereas the <i>lack</i> of FAS predicts freedom from disease and overall survival [<a class="bk_pop" href="#ml356.r8">8</a>]. FAS is also linked to poor prognosis in soft tissue sarcomas [<a class="bk_pop" href="#ml356.r6">6</a>], Wilms tumor [<a class="bk_pop" href="#ml356.r15">15</a>], renal cell carcinoma [<a class="bk_pop" href="#ml356.r16">16</a>], and squamous cell carcinoma of the tongue [<a class="bk_pop" href="#ml356.r17">17</a>]. The correlation between expression of FAS and poor prognosis strongly suggests that this enzyme is mechanistically linked to disease progression, providing a strong rationale for pursuing the development of FAS inhibitors.</p><p>Indeed, many other studies show that <i>the requirement for FAS for tumor growth and survival is unequivocal</i>. Dozens of studies show that knockdown of FAS with siRNA arrests the tumor cell cycle at G1/S and causes tumor cell apoptosis. We will not review the literature on the requirement for FAS here because much of it is directly supported by our prior publications [<a class="bk_pop" href="#ml356.r18">18</a>,<a class="bk_pop" href="#ml356.r5">5</a>,<a class="bk_pop" href="#ml356.r19">19</a>-<a class="bk_pop" href="#ml356.r24">24</a>]. Also, more than two dozen review articles have been written on this topic where strong arguments are made for FAS as a drug target (a good sampling of these reviews [<a class="bk_pop" href="#ml356.r25">25</a>-<a class="bk_pop" href="#ml356.r29">29</a>]). Several studies, including one by Prof. Smith, the assay provider [<a class="bk_pop" href="#ml356.r30">30</a>], show that inhibitors of FAS may also work well to sensitize tumor cells to other widely used anti-cancer drugs including paclitaxel and Herceptin [<a class="bk_pop" href="#ml356.r30">30</a>-<a class="bk_pop" href="#ml356.r36">36</a>]There are two primary uses for the probe described here; i) to assist in the study of FAS in cell-based studies, and ii) to serve as the foundation for further medicinal chemistry efforts to develop a drug that selectively targets human FAS.</p><p>FAS condenses acetyl CoA with malonyl CoA In the first step in its reaction cycle. Subsequent rounds of condensation of acetyl CoA produce palmitate, which remains bound to the acyl carrier domain of FAS. The thioesterase domain, the target of the probe described here, cleaves the thioester bond with the acyl carrier protein, liberating palmitate from the enzyme. By blocking the active site of the FAS thioesterase, the probe prevents cleavage of palmitate from the acyl carrier protein, and halts palmitate biosynthesis.</p><div id="ml356.f2" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%201.%20Schematic%20diagram%20of%20FAS%20showing%20enzymatic%20steps%20involved%20in%20fatty%20acid%20biosynthesis%20leading%20to%20palmitic%20acid.&p=BOOKS&id=189923_ml356f2.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK189923/bin/ml356f2.jpg" alt="Figure 1. Schematic diagram of FAS showing enzymatic steps involved in fatty acid biosynthesis leading to palmitic acid." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 1</span><span class="title">Schematic diagram of FAS showing enzymatic steps involved in fatty acid biosynthesis leading to palmitic acid</span></h3><div class="caption"><p>FAS is comprised of six enzymatic domains and an acyl-carrier protein (ACP) that work together to perform the following chemical steps leading to synthesis of palmitate: The malonyl/acetyl transferase domain (1) transfers an acetyl group onto the ACP. It is then translocated to the active-site cysteine by α-ketoacyl synthase (2). This position, marked “R”, also serves as the loading position for the growing acyl chain in subsequent iterations. The malonyl/acetyl transferase domain (1) then transfers a malonyl group to the ACP, and the two are condensed (2) into a four-carbon product bound to the enzyme through the thiol of the ACP. The ketoacyl reductase (3) reduces the ketone at C-3 to an alcohol. The dehydrase (4) further reduces the alcohol to an alkene. The enoyl reductase domain (5) further reduces the alkene bond to an alkane, and the ACP-bound chain is translocated back to the active-site cysteine (2). Steps 2-5 are then repeated six times to yield a 16-carbon, fully saturated palmitic acid bound to the ACP. The palmitate is released from FAS by the enzyme's intrinsic thioesterase domain (green arrow), which is the target of this study.</p></div></div><p>Several key questions on the function of FAS can be addressed by using <a href="/pcsubstance/?term=ML356[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML356</a> in cell-based studies. First, there is no information on how inhibition of FAS might impacts flux through other branches of central carbon metabolism (i.e. glycolysis, TCA cycle, glutaminolysis etc.). It is reasonable to hypothesize that a FAS blockade will increase the levels of the two key substrates, acetyl Co A and malonyl CoA. The accumulation of these metabolites is likely to feedback into glycolysis and/or the TCA cycle. Levels of the NADPH cofactor are also likely to increase, perhaps inducing a cellular redox stress. <a href="/pcsubstance/?term=ML356[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML356</a> makes it possible to study these issues.</p><p>In addition, there is not a good understanding of how inhibition of FAS elicits apoptosis in tumor cells. While we know that FAS blockade induces cell death in breast cancer cells through the extraneous apoptotic pathway (caspase 8), it is not at all clear why inhibition of FAS causes this effect. It may relate to either lack of cellular palmitate, or redox stress mentioned previously. <a href="/pcsubstance/?term=ML356[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML356</a> makes it possible to study these issues.</p><p>There are also studies indicating the inhibition of FAS interferes with signaling through KDR, the VEGF receptor, and thereby inhibits angiogenesis [<a class="bk_pop" href="#ml356.r37">37</a>]. However, the mechanism of inactivation of KDR has not been studied in any detail. The pharmacologic approach is especially important in studying angiogenesis because siRNA and shRNA methods are fraught with difficulty in primary cultures of endothelial cells, and are extremely time-consuming and expensive in animal models. <a href="/pcsubstance/?term=ML356[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML356</a> makes it possible to understand the molecular detail connecting inhibition of FAS with KDR and VEGF signaling.</p><p>There is now widespread interest in developing precision (or personalized) medicine, especially for oncology. Gene expression and deep sequencing studies have now identified tumor cell lines that are correlates of the major sub-types of most human cancers. <a href="/pcsubstance/?term=ML356[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML356</a> can be used to determine which tumor subtypes and sensitive to a FAS blockade, and to correlate this sensitivity with specific gene expression, or even genomic signatures. Such studies will go a long way toward understanding the genetic basis of the FAS-dependent phenotype in tumors.</p><p><a href="/pcsubstance/?term=ML356[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML356</a> could also be useful for screening for compounds (even existing drugs) that synergize (or are additive) with FAS blockade in halting growth and killing tumor cells, and/or endothelial cells.</p><p><a href="/pcsubstance/?term=ML356[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML356</a> can also serve as the lead structure for further medicinal chemistry to create additional probes to study the function of FAS <i>in vivo</i>. To our knowledge, no thioesterase (TE) has ever been targeted for drug development. Inhibitors/probes against FAS will be of value for research purposes in the development of single agent therapy against tumors, potentially as chemo-sensitizers. They may also show promise as anti-angiogenic and anti-obesity agents. Follow on derivatives of <a href="/pcsubstance/?term=ML356[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML356</a> with good bioavailablity and pharmacokinetic properties will facilitate the first rigorous test of the idea that fatty acid synthase is necessary for tumor onset and/or progression in both xenograft, and genetic models of cancer. Similar studies can be done in animal models of angiogenesis, and obesity.</p></div><div id="ml356.s3"><h2 id="_ml356_s3_">2. Materials and Methods</h2><div id="ml356.s4"><h3>2.1. Assays</h3><p><b>The detailed description and protocols for the primary HTS and additional assays can be found in the “Assay Description” section in the PubChem BioAssay <i>(<a href="http://pubchem.ncbi.nlm.nih.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">http://pubchem.ncbi.nlm.nih.gov/</a>)</i> view under the AIDs as listed in</b>
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<a class="figpopup" href="/books/NBK189923/table/ml356.t2/?report=objectonly" target="object" rid-figpopup="figml356t2" rid-ob="figobml356t2">Table 2</a>.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml356t2"><a href="/books/NBK189923/table/ml356.t2/?report=objectonly" target="object" title="Table 2" class="img_link icnblk_img figpopup" rid-figpopup="figml356t2" rid-ob="figobml356t2"><img class="small-thumb" src="/books/NBK189923/table/ml356.t2/?report=thumb" src-large="/books/NBK189923/table/ml356.t2/?report=previmg" alt="Table 2. Summary of Assays and AIDs." /></a><div class="icnblk_cntnt"><h4 id="ml356.t2"><a href="/books/NBK189923/table/ml356.t2/?report=objectonly" target="object" rid-ob="figobml356t2">Table 2</a></h4><p class="float-caption no_bottom_margin">Summary of Assays and AIDs. </p></div></div></div><div id="ml356.s5"><h3>2.2. Probe Chemical Characterization</h3><p><b>Chemical name of probe compound.</b> The IUPAC name of the probe [<a href="/pcsubstance/?term=ML356[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML356</a>] is 2-ethyl-N-(4-(4-(morpholinosulfonyl)phenyl)thiazol-2-yl)butanamide (<i>PubChem currently does not have an IUPAC name</i>). The actual batch prepared, tested and submitted to the MLSMR is <a href="https://pubchem.ncbi.nlm.nih.gov/substance/160658425" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 160658425</a> corresponding to CID 70680643.</p><div id="ml356.f3" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%202.%20Structure%20of%20ML356.&p=BOOKS&id=189923_ml356f3.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK189923/bin/ml356f3.jpg" alt="Figure 2. Structure of ML356." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 2</span><span class="title">Structure of ML356</span></h3></div><div id="ml356.s6"><h4>Synthesis and Structural Verification of probe SID 160658425 corresponding to CID 70680643 (ML356) – See <a class="figpopup" href="/books/NBK189923/figure/ml356.f4/?report=objectonly" target="object" rid-figpopup="figml356f4" rid-ob="figobml356f4">Scheme 1</a></h4><div id="ml356.f4" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Scheme%201.%20Synthesis%20of%20ML356%2C%20conditions%3A%20a.%20Morpholine%2C%20DIPEA%2C%20DCM%2C%20RT%2C%20overnight%20(78%25)%3B%20b.%20Bromine%2C%20HBr%2045%25%20solution%2C%20chloroform%2C%200%20%B0C%20to%20RT%2C%20overnight%20(60%25)%3B%20c.%20Thiourea%2C%20NaHCO3%2C%20THF%2C%20RT%2C%20overnight%20(83%25)%3B%20d.%202-Ethylbutyoric%20chloride%2C%20dry%20pyridine%2C%20dry%20dichloromethane%2C%2060%B0C%20reflux%2C%20overnight%20(65%25).&p=BOOKS&id=189923_ml356f4.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK189923/bin/ml356f4.jpg" alt="Scheme 1. Synthesis of ML356, conditions: a. Morpholine, DIPEA, DCM, RT, overnight (78%); b. Bromine, HBr 45% solution, chloroform, 0 °C to RT, overnight (60%); c. Thiourea, NaHCO3, THF, RT, overnight (83%); d. 2-Ethylbutyoric chloride, dry pyridine, dry dichloromethane, 60°C reflux, overnight (65%)." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Scheme 1</span><span class="title">Synthesis of ML356, conditions: a. Morpholine, DIPEA, DCM, RT, overnight (78%); b. Bromine, HBr 45% solution, chloroform, 0 °C to RT, overnight (60%); c. Thiourea, NaHCO<sub>3</sub>, THF, RT, overnight (83%); d. 2-Ethylbutyoric chloride, dry pyridine, dry dichloromethane, 60°C reflux, overnight (65%)</span></h3></div><div id="ml356.f5" class="figure bk_fig"><h3><span class="label">Figure 3</span><span class="title"><sup>1</sup>H NMR and LC-MS spectra of ML356</span></h3><div id="ml356.f6" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%203A.%201H%20NMR%20Spectrum%20of%20ML356%20(500%20MHz%2C%20Methanol-d4).&p=BOOKS&id=189923_ml356f5.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK189923/bin/ml356f5.jpg" alt="Figure 3A. 1H NMR Spectrum of ML356 (500 MHz, Methanol-d4)." class="tileshop" title="Click on image to zoom" /></a></div><h4><span class="label">Figure 3A</span><span class="title">1H NMR Spectrum of ML356 (500 MHz, Methanol-<i>d</i><sub>4</sub>)</span></h4></div><div id="ml356.f7" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%203B.%2013C%20NMR%20Spectrum%20of%20ML356%20(125%20MHz%2C%20Methanol-d4).&p=BOOKS&id=189923_ml356f6.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK189923/bin/ml356f6.jpg" alt="Figure 3B. 13C NMR Spectrum of ML356 (125 MHz, Methanol-d4)." class="tileshop" title="Click on image to zoom" /></a></div><h4><span class="label">Figure 3B</span><span class="title"><sup>13</sup>C NMR Spectrum of ML356 (125 MHz, Methanol-<i>d</i><sub>4</sub>)</span></h4></div><div id="ml356.f8" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%203C.%20LC%2FMS%20for%20ML356%20and%20MS%20scan%20(inset).&p=BOOKS&id=189923_ml356f7.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK189923/bin/ml356f7.jpg" alt="Figure 3C. LC/MS for ML356 and MS scan (inset)." class="tileshop" title="Click on image to zoom" /></a></div><h4><span class="label">Figure 3C</span><span class="title">LC/MS for ML356 and MS scan (inset)</span></h4></div></div><p><b>Solubility and Stability of probe <a href="/pcsubstance/?term=ML356[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML356</a> in PBS at room temperature:</b> The solubility of <a href="/pcsubstance/?term=ML356[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML356</a> was investigated in aqueous buffers at room temperature (see <a class="figpopup" href="/books/NBK189923/figure/ml356.f9/?report=objectonly" target="object" rid-figpopup="figml356f9" rid-ob="figobml356f9">Figure 4</a>). As noted in the <i>Summary of <b>in vitro</b> ADME/T properties</i> (see <a class="figpopup" href="/books/NBK189923/table/ml356.t3/?report=objectonly" target="object" rid-figpopup="figml356t3" rid-ob="figobml356t3">Table 4</a>), <a href="/pcsubstance/?term=ML356[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML356</a> has a poor solubility in aqueous buffers. However, <a href="/pcsubstance/?term=ML356[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML356</a> appears very chemically stable in both PBS and 1:1 PBS:acetonitrile,</p><div id="ml356.f9" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%204.%20Stability%20of%20ML356%20in%201%D7%20PBS%20and%2050%3A50%20PBS%3AACN.&p=BOOKS&id=189923_ml356f8.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK189923/bin/ml356f8.jpg" alt="Figure 4. Stability of ML356 in 1× PBS and 50:50 PBS:ACN." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 4</span><span class="title">Stability of ML356 in 1× PBS and 50:50 PBS:ACN</span></h3></div><div id="ml356.t3" class="table"><h3><span class="label">Table 4</span><span class="title">Summary of <i>in vitro</i> ADME Properties of FAS-TE inhibitor probe ML356</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK189923/table/ml356.t3/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml356.t3_lrgtbl__"><table class="no_margin"><tbody><tr><td colspan="2" rowspan="1" style="text-align:left;vertical-align:middle;"><b>Aqueous Solubility</b> in pION's buffer (μg/mL) <i>[μM]</i><sup><a class="bk_pop" href="#ml356.tfn1">a</a></sup> pH 5.0/6.2/7.4</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.19/0.06/0.13<br /><i>[0.45 /0.14 /0.31]</i></td></tr><tr><td colspan="2" rowspan="1" style="text-align:left;vertical-align:middle;"><b>Aqueous Solubility</b> in 1× PBS, pH 7.4 (μg/mL) <i>[μM]</i><sup><a class="bk_pop" href="#ml356.tfn1">a</a></sup></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.02 <i>[0.05]</i></td></tr><tr><td colspan="2" rowspan="1" style="text-align:left;vertical-align:middle;"><b>Chemical Stability</b> in 1× PBS pH 7.4 / with 50% ACN (% remaining after 48hrs)</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">100/100</td></tr><tr><td colspan="2" rowspan="1" style="text-align:left;vertical-align:middle;"><b>PAMPA Permeability</b>, Pe (×10<sup>-6</sup> cm/s) Donor pH: 5.0 / 6.2 / 7.4 Acceptor pH: 7.4</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">914/961/653</td></tr><tr><td rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;"><b>Plasma Protein Binding</b> (% Bound)</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Human 1 μM / 10 μM</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">96.60/97.47</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Mouse 1 μM / 10 μM</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">96.19/96.63</td></tr><tr><td colspan="2" rowspan="1" style="text-align:left;vertical-align:middle;"><b>Plasma Stability</b> (% Remaining at 3 hrs) Human/Mouse</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">100/100</td></tr><tr><td colspan="2" rowspan="1" style="text-align:left;vertical-align:middle;"><b>Hepatic Microsome Stability</b> (% Remaining at 1hr) Human/Mouse</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">4.93/6.37</td></tr><tr><td colspan="2" rowspan="1" style="text-align:left;vertical-align:middle;"><b>Toxicity</b> Towards Fa2N-4 Immortalized Human Hepatocytes LC<sub>50</sub> (μM)</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">>50</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>a</dt><dd><div id="ml356.tfn1"><p class="no_margin">Solubility also expressed in molar units (μM) as indicated in <i>italicized [bracketed values],</i> in addition to more traditional μg/mL units.</p></div></dd></dl></div></div></div><p><b>MLS# verifying submission of probe molecule and five related samples submitted to the SMR collection.</b> This probe is not commercially available. Samples of the probe <a href="/pcsubstance/?term=ML356[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML356</a> (>25 mg), and five analogs of each (>20 mg), synthesized at SBCCG were submitted to MLSMR (<a class="figpopup" href="/books/NBK189923/table/ml356.t4/?report=objectonly" target="object" rid-figpopup="figml356t4" rid-ob="figobml356t4">Table 3</a>, > 25 mg will be provided to the Assay Provider (Dr. Jeffery Smith) and >50 mg of the probe will be retained by SBCCG for future requests.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml356t4"><a href="/books/NBK189923/table/ml356.t4/?report=objectonly" target="object" title="Table 3" class="img_link icnblk_img figpopup" rid-figpopup="figml356t4" rid-ob="figobml356t4"><img class="small-thumb" src="/books/NBK189923/table/ml356.t4/?report=thumb" src-large="/books/NBK189923/table/ml356.t4/?report=previmg" alt="Table 3. Probe and Analog Submissions to MLSMR (BioFocus DPI) for FAS Inhibitors ML356." /></a><div class="icnblk_cntnt"><h4 id="ml356.t4"><a href="/books/NBK189923/table/ml356.t4/?report=objectonly" target="object" rid-ob="figobml356t4">Table 3</a></h4><p class="float-caption no_bottom_margin">Probe and Analog Submissions to MLSMR (BioFocus DPI) for FAS Inhibitors ML356. </p></div></div></div></div><div id="ml356.s7"><h3>2.3. Probe Preparation</h3><p><b>Synthesis of probe <a href="/pcsubstance/?term=ML356[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML356</a></b> was readily prepared in 4 steps from commercially available starting materials. (Compounds are numbers as in <a class="figpopup" href="/books/NBK189923/figure/ml356.f4/?report=objectonly" target="object" rid-figpopup="figml356f4" rid-ob="figobml356f4">Scheme 1</a>)</p><div id="ml356.s8"><h4>Preparation of 1-(4-(morpholinosulfonyl)phenyl)ethanone [2]</h4><div class="graphic"><img src="/books/NBK189923/bin/ml356ig1.jpg" alt="Image ml356ig1.jpg" /></div><p>4-Acetylbenzenesufonyl chloride <b>1</b> (3.5 g, 16 mmol) and 3 ml of DIPEA were dissolved in 100 ml of dichloromethane. To the resulting mixture was added morpholine (4.0 mL, 46 mmol) and the reaction was stirred at room temperature overnight. When the reaction was determined to be complete by HPLC, the reaction mixture was concentrated under reduced pressure. The resulting oil was chromatographed on silica gel and eluted with ethyl acetate and dichoromethane (0:100 to 30:70 gradient) to yield 3.4 g of product <b>2</b> (78 % yield). MS (EI) m/z 270 (M+1).</p></div><div id="ml356.s9"><h4>Preparation of 2-bromo-1-(4-(morpholinosulfonyl)phenyl)ethanone [3]</h4><div class="graphic"><img src="/books/NBK189923/bin/ml356ig2.jpg" alt="Image ml356ig2.jpg" /></div><p>1-(4-(morpholinosulfonyl)phenyl)ethanone <b>2</b> (3.4 g, 12.6 mmol) and 3 drops of HBr 45% solution were dissolved in 100 ml of chloroform in an ice-water bath. To the resulting mixture was added dropwise bromine (0.64 ml, 12.4 mmol) in 5 ml of chloroform and the reaction was stirred overnight, gradually warming to room temperature. When the reaction was determined to be complete by HPLC, the reaction mixture was washed with a sat. sodium thiosulfate solution and separated. The organic layer was dried and concentrated under reduced pressure. The resulting oil was chromatographed on silica gel and eluted with ethyl acetate and dichoromethane (0:100 to 30:70 gradient) to yield 2.6 g of product <b>3</b> (60 % yield). MS (EI) m/z 350 (M+1). <sup>1</sup>H NMR (400 MHz, CDCl3) δ(ppm) 3.04 (m, 4H), 3.75 (m, 4H), 4.45 (m, 2H), 7.87 (d, 2H), 8.15 (d, 2H).</p></div><div id="ml356.s10"><h4>Preparation of 4-(4-(morpholinosulfonyl)phenyl)thiazol-2-amine [2]</h4><div class="graphic"><img src="/books/NBK189923/bin/ml356ig3.jpg" alt="Image ml356ig3.jpg" /></div><p>2-bromo-1-(4-(morpholinosulfonyl)phenyl)ethanone <b>3</b> (2.6 g, 7.4 mmol) and sodium bicarbonate (1.3 g, 16 mmol) were mixed in 100 ml of dry THF. To the resulting mixture was added thiourea (1.0 g, 13 mmol) and the reaction was stirred at room temperature overnight. When the reaction was determined to be complete by HPLC, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane and washed with water. The organic layer was dried and concentrated and was chromatographed on silica gel and eluted with ethyl acetate and dichoromethane (0:100 to 40:60 gradient) to yield 2.0 g of product <b>4</b> (83 % yield). <sup>1</sup>H NMR (400 MHz, DMSO-d6) δ(ppm) 2.86 (m, 4H), 3.62 (m, 4H), 7.18 (s, 2H), 7.30 (s, 1H), 7.70 (d, 2H), 8.03 (d, 2H). <sup>13</sup>C NMR (400 MHz, DMSO-d6) δ(ppm) 39.9, 65.2, 105.0, 126.1, 128.1, 132.4, 139.2, 148.1, 168.5. MS (EI) m/z 326 (M+1).</p></div><div id="ml356.s11"><h4>Preparation of 2-ethyl-N-(4-(4-(morpholinosulfonyl)phenyl)thiazol-2-yl)butanamide [3]</h4><div class="graphic"><img src="/books/NBK189923/bin/ml356ig4.jpg" alt="Image ml356ig4.jpg" /></div><p>4-(4-(morpholinosulfonyl)phenyl)thiazol-2-amine <b>4</b> (0.5 g, 1.5 mmol) and 1.0 mL of dry pyridine were dissolved in dry dichoromethane (50 mL). To the resulting mixture was added 2-ethylbutyryl chloride (0.5 mL, 3.7 mmol) and the reaction was refluxed at 60 °C overnight. When the reaction was determined to be complete by HPLC, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting oil was chromatographed on silica gel and eluted with ethyl acetate and dichoromethane (0:100 to 20:80 gradient) to yield 0.42 g of product <b>5</b> (65 % yield). <sup>1</sup>H NMR (400 MHz, CDCl3) δ(ppm) 0.91 (m, 6H), 1.61 (m, 2H), 1.71 (m, 2H), 2.20 (m, 1H), 3.04 (m, 4H), 3.75 (m, 4H), 7.33 (s, 1H), 7.85 (d, 2H), 8.02 (d, 2H), 9.57 (s, 1H). <sup>13</sup>C NMR (400 MHz, CDCl3) δ(ppm) 11.9, 25.5, 46.0, 50.9, 66.1, 110.6, 126.5, 128.4, 133.9, 138.8, 147.7, 158.3, 174.2. MS (EI) m/z 424 (M+1).</p></div></div></div><div id="ml356.s12"><h2 id="_ml356_s12_">3. Results</h2><div id="ml356.s13"><h3>3.1. Dose Response Curves for Probe</h3><p>The <i>in vitro</i> biochemical potency (IC<sub>50</sub>) <a href="/pcsubstance/?term=ML356[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML356</a> against FAS-TE is 334 nM (<a class="figpopup" href="/books/NBK189923/figure/ml356.f14/?report=objectonly" target="object" rid-figpopup="figml356f14" rid-ob="figobml356f14">Figure 5</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml356f14" co-legend-rid="figlgndml356f14"><a href="/books/NBK189923/figure/ml356.f14/?report=objectonly" target="object" title="Figure 5" class="img_link icnblk_img figpopup" rid-figpopup="figml356f14" rid-ob="figobml356f14"><img class="small-thumb" src="/books/NBK189923/bin/ml356f13.gif" src-large="/books/NBK189923/bin/ml356f13.jpg" alt="Figure 5. Potency of ML356 against the thioester domain of fatty acid synthase (FAS-TE)." /></a><div class="icnblk_cntnt" id="figlgndml356f14"><h4 id="ml356.f14"><a href="/books/NBK189923/figure/ml356.f14/?report=objectonly" target="object" rid-ob="figobml356f14">Figure 5</a></h4><p class="float-caption no_bottom_margin">Potency of ML356 against the thioester domain of fatty acid synthase (FAS-TE). </p></div></div></div><div id="ml356.s14"><h3>3.5. Cellular Activity</h3><p>The ability of probes to block biosynthesis of palmitate in whole cells (prostate cancer PC-3 cells) was measured by feeding cells isotopically labeled glucose (<sup>13</sup>C-glucose) and measuring the incorporation of <sup>13</sup>C into palmitate by GC-MS. These assays indicate the inhibitory activity of the probe <a href="/pcsubstance/?term=ML356[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML356</a> and active analog in whole cells (<a class="figpopup" href="/books/NBK189923/figure/ml356.f15/?report=objectonly" target="object" rid-figpopup="figml356f15" rid-ob="figobml356f15">Figure 6</a>), whereas inactive analog (MLS-0472100) did not inhibit palmitate biosynthesis.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml356f15" co-legend-rid="figlgndml356f15"><a href="/books/NBK189923/figure/ml356.f15/?report=objectonly" target="object" title="Figure 6" class="img_link icnblk_img figpopup" rid-figpopup="figml356f15" rid-ob="figobml356f15"><img class="small-thumb" src="/books/NBK189923/bin/ml356f14.gif" src-large="/books/NBK189923/bin/ml356f14.jpg" alt="Figure 6. FAS inhibitors block palmitate biosynthesis in PC-3 cells." /></a><div class="icnblk_cntnt" id="figlgndml356f15"><h4 id="ml356.f15"><a href="/books/NBK189923/figure/ml356.f15/?report=objectonly" target="object" rid-ob="figobml356f15">Figure 6</a></h4><p class="float-caption no_bottom_margin">FAS inhibitors block palmitate biosynthesis in PC-3 cells. <i>Prostate cancer PC-3 cell were incubated with 20μM of FAS inhibitors and</i> labeled with [U-13C]-glucose for 24h, pH 7.8. The incorporation of 13C into palmitate from labeled glucose was <a href="/books/NBK189923/figure/ml356.f15/?report=objectonly" target="object" rid-ob="figobml356f15">(more...)</a></p></div></div></div><div id="ml356.s15"><h3>3.3. Profiling Assays</h3><p><a href="/pcsubstance/?term=ML356[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML356</a> was evaluated in a detailed <i>in vitro</i> pharmacology screen as shown in <a class="figpopup" href="/books/NBK189923/table/ml356.t3/?report=objectonly" target="object" rid-figpopup="figml356t3" rid-ob="figobml356t3">Table 4</a>:</p><p><a href="/pcsubstance/?term=ML356[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML356</a> has poor solubility in aqueous media.</p><p>The PAMPA (<b>P</b>arallel <b>A</b>rtificial <b>M</b>embrane <b>P</b>ermeability <b>A</b>ssay) assay is used as an <i>in vitro</i> model of passive, transcellular permeability. An artificial membrane immobilized on a filter is placed between a donor and acceptor compartment. At the start of the test, drug is introduced in the donor compartment. Following the permeation period, the concentration of drug in the donor and acceptor compartments is measured using UV spectroscopy. <a href="/pcsubstance/?term=ML356[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML356</a> exhibited very good permeability across a range of pH of the donor compartment.</p><p>Plasma protein binding is a measure of a drug's efficiency to bind to the proteins within blood plasma. The less bound a drug is, the more efficiently it can traverse cell membranes or diffuse. Highly plasma protein bound drugs are confined to the vascular space, thereby having a relatively low volume of distribution. In contrast, drugs that remain largely unbound in plasma are generally available for distribution to other organs and tissues. <a href="/pcsubstance/?term=ML356[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML356</a> was highly plasma protein bound.</p><p>Plasma stability is a measure of the stability of small molecules and peptides in plasma and is an important parameter, which can strongly influence the <i>in vivo</i> efficacy of a test compound. Drug candidates are exposed to enzymatic processes (proteinases, esterases) in plasma, and they can undergo intramolecular rearrangement or bind irreversibly (covalently) to proteins. <a href="/pcsubstance/?term=ML356[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML356</a> showed good stability in both human plasma and mouse plasma.</p><p>The microsomal stability assay is commonly used to rank compounds according to their metabolic stability. This assay addresses the pharmacologic question of how long the parent compound will remain circulating in plasma within the body. <a href="/pcsubstance/?term=ML356[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML356</a> showed poor stability in human and mouse liver microsomes.</p><p><a href="/pcsubstance/?term=ML356[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML356</a> showed no toxicity (>50 μM) towards immortalized Fa2-N4 human hepatocytes.</p></div></div><div id="ml356.s16"><h2 id="_ml356_s16_">4. Discussion</h2><p>The ultimate objective of this proposal is to develop drug-like inhibitors of the thioesterase (TE) domain of fatty acid synthase (FAS: NP004095.4, GI:41872631), an enzyme that is essential for growth of solid tumors. We hypothesize that such compounds will block tumor growth <i>in vivo</i> because FAS is up-regulated in all the major solid tumors [<a class="bk_pop" href="#ml356.r18">18</a>], and in most cases its expression is indicative of poor prognosis [<a class="bk_pop" href="#ml356.r1">1</a>,<a class="bk_pop" href="#ml356.r2">2</a>,<a class="bk_pop" href="#ml356.r11">11</a>]. Knockdown of FAS with siRNA halts tumor cell proliferation and selectively induces apoptosis of tumor cells [<a class="bk_pop" href="#ml356.r30">30</a>,<a class="bk_pop" href="#ml356.r33">33</a>]. The correlation between expression of FAS and poor prognosis strongly suggests that this enzyme is mechanistically linked to disease progression, providing a strong rationale for developing inhibitors of FAS. The overarching objective of this study is to identify novel inhibitors of the thioesterase domain of FAS that are potent, selective, and stable.</p><p>To our knowledge, no thioesterase (TE) has ever been targeted for drug development. Consequently, the unique enzymatic target and the new chemical entities that will be developed point to the novelty of the study. The work proposed here is likely to pave the way for discovery of probes and drugs to target thioesterases similar to those involved in polyketide synthesis, mycolic acid biosynthesis from <i>Mycobacterium tuberculosis</i>, siderophore biosynthesis in bacteria, etc. This illustrates the metabolic context of the FAS enzyme and highlights the rationale for the druggabiiity of this target and selectivity against other off-target enzymes.</p><div id="ml356.s17"><h3>4.1. Comparison to Existing Art and How the New Probe is an Improvement</h3><p><i>Several inhibitors of human FAS have been reported, but almost all of these have serious limitations including, complex synthetic procedures, poor solubility, lack of potency, covalent modes of binding, and perhaps most importantly, lack of selectivity (for review see [</i><a class="bk_pop" href="#ml356.r27">27</a><i>]).</i> The three most commonly used FAS antagonists are cerulenin (or its derivative C75), and orlistat.</p><p>Cerulenin a fatty-acid like dodecadienamide is natural product with antibiotic properties, that was found to inhibit human FAS and to be cytotoxic to tumor cells [<a class="bk_pop" href="#ml356.r2">2</a>]. However, cerulenin is an irreversible inhibitor (epoxide) of FAS β-ketoacyl synthase, and is not selective for FAS; it affects many other processes (protein acylation, cholesterol synthesis and proteolysis). C75 is a synthetic analog of cerulenin that blocks tumor-cell proliferation and induces apoptosis, has anti-tumor activity in mouse models of androgen-independent prostate cancer [<a class="bk_pop" href="#ml356.r38">38</a>], breast cancer [<a class="bk_pop" href="#ml356.r3">3</a>], mesothelioma [<a class="bk_pop" href="#ml356.r39">39</a>], and ovarian cancer [<a class="bk_pop" href="#ml356.r12">12</a>]. But C75 is a weakly potent (mM-range) inhibitor of FAS β-ketoacyl synthase, acid still contains obviously reactive moieties (lactone and electrophilic <i>exo</i> double bond). C75 also lacks selectivity for FAS; it is a potent agonist of carnitine palmitoyl transferase 1 (CPT1), and through this action it simulates fatty acid oxidation and the production of ATP [<a class="bk_pop" href="#ml356.r40">40</a>], and causes weight loss in animals. So C75 lacks selectivity, and has other known targets, making it impossible to use this compound to draw conclusions on FAS.</p><p>The assay provider's group (Dr. Smith) has published several papers on the use of orlistat as a FAS inhibitor [<a class="bk_pop" href="#ml356.r41">41</a>,<a class="bk_pop" href="#ml356.r42">42</a>]. Importantly, orlistat is not specific to FAS; its anti-obesity effect has been associated with irreversible inactivation of gastric and pancreatic lipases. Although orlistat is an interesting lead antagonist of FAS, it contains a reactive β-lactone that is not optimal for drug/probe development. The reactive β-lactone leads to dead end inhibition of FAS, so once the drug is on board, removal of the agent is dependent upon the half-life of FAS; halting administration of the drug is of little value if any acute toxicity were dose-limiting. Furthermore, the reactive group is likely to react with other proteins/enzymes, as well as with plasma and tissue constituents, leading to a complicated pharmacokinetic profile. Finally, orlistat has poor solubility (cLogP = ∼14), making it almost impossible to determine the precise dose of the compounds that inhibits FAS in cells or in animals. Dr. Smiths group, along with Dan Romo's group at Texas A&M attempted to generate more soluble and selective orlistat-derivatives, but complex synthetic procedures hindered this effort [<a class="bk_pop" href="#ml356.r41">41</a>-<a class="bk_pop" href="#ml356.r44">44</a>].</p><p>The green tea polyphenol epigallocatechin-3-gallate (EGCG) and other naturally occurring flavonoids (i.e., luteolin, quercetin, and kaempferol), as well as the antibiotic triclosan, are reported to inhibit FAS and induce apoptotic cell death [<a class="bk_pop" href="#ml356.r28">28</a>]. Another polyphenol/polycatechol compound G284CM has been reported to inhibit FAS; however, its exact structure is not available, polyphenols are prone to oxidation and oligomerization, and no proof of its direct interaction with FAS has been disclosed. Irrespective of G284CM primary target, chemical liabilities affiliated with polyphenol/catechol scaffold, makes it un-drug-like. Orlistat, an antiobesity drug, irreversibly modifies FAS TE domain active site. However, it is not specific to FAS; its antiobesity effect has been associated with irreversible inactivation of gastric and pancreatic lipases.</p><p>In summary, all these compounds, while known to inhibit FAS irreversibly, are certainly not selective for FAS as they all have other reported targets consistent with the non-specificity of alkylation prone reactive moieties. Finally, there is no known <u><i>reversible</i></u> inhibitor of thioesterase domain of FAS to date.</p><p>A recent SciFinder search conducted by Dr. Anthony Pinkerton on November 27, 2011, found an additional recent report of a FAS inhibitor, the antibiotic platensimycin (<a class="figpopup" href="/books/NBK189923/figure/ml356.f16/?report=objectonly" target="object" rid-figpopup="figml356f16" rid-ob="figobml356f16">Figure 7</a>). Platensimycin has been shown to concentrate in the liver after oral administration to mice, and potently inhibits hepatic <i>de novo</i> lipogenesis, reduces fatty acid oxidation, and increases glucose oxidation in mouse models of diabetes [<a class="bk_pop" href="#ml356.r45">45</a>]. It, however, is a natural product of high molecular weight (m.w. 441) and complex structure originally isolated as broad spectrum Gram-positive antibiotic produced and isolated from <i>Streptomyces platensis</i> [<a class="bk_pop" href="#ml356.r46">46</a>]. Synthesis yields a racemic mixture, therefore, simpler chemically tractable probes are still needed. Nor is there any evidence of its selectivity for FAS over other human thioesterases.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml356f16" co-legend-rid="figlgndml356f16"><a href="/books/NBK189923/figure/ml356.f16/?report=objectonly" target="object" title="Figure 7" class="img_link icnblk_img figpopup" rid-figpopup="figml356f16" rid-ob="figobml356f16"><img class="small-thumb" src="/books/NBK189923/bin/ml356f15.gif" src-large="/books/NBK189923/bin/ml356f15.jpg" alt="Figure 7. Structure of Platensimycin." /></a><div class="icnblk_cntnt" id="figlgndml356f16"><h4 id="ml356.f16"><a href="/books/NBK189923/figure/ml356.f16/?report=objectonly" target="object" rid-ob="figobml356f16">Figure 7</a></h4><p class="float-caption no_bottom_margin">Structure of Platensimycin. </p></div></div><p>A more recent SciFinder search conducted by Dr. Robert J. Ardecky on April 1, 2013, found one new reference that describes compounds that inhibit the recombinant domain of FASN. Some compounds show the ability to inhibit FASN in living cells and some compounds showed the ability to inhibit <i>in vitro</i> cancer cell growth. The general structure of these compounds is illustrated in <a class="figpopup" href="/books/NBK189923/figure/ml356.f17/?report=objectonly" target="object" rid-figpopup="figml356f17" rid-ob="figobml356f17">Figure 8</a>: The IC<sub>50</sub> values of the best compounds were in 2.35 μM to 10 μM range. (PCT Int. Appl. (2012), WO 2012064632 A1 20120518)</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml356f17" co-legend-rid="figlgndml356f17"><a href="/books/NBK189923/figure/ml356.f17/?report=objectonly" target="object" title="Figure 8" class="img_link icnblk_img figpopup" rid-figpopup="figml356f17" rid-ob="figobml356f17"><img class="small-thumb" src="/books/NBK189923/bin/ml356f16.gif" src-large="/books/NBK189923/bin/ml356f16.jpg" alt="Figure 8. Markush structure from PCT Int. Appl. (2012), WO 2012064632 A1 20120518)." /></a><div class="icnblk_cntnt" id="figlgndml356f17"><h4 id="ml356.f17"><a href="/books/NBK189923/figure/ml356.f17/?report=objectonly" target="object" rid-ob="figobml356f17">Figure 8</a></h4><p class="float-caption no_bottom_margin">Markush structure from PCT Int. Appl. (2012), WO 2012064632 A1 20120518). </p></div></div><p>In this report we have identified the most potent and first-in-class FAS TE Inhibitor known, <a href="/pcsubstance/?term=ML356[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML356</a> (CID 70680643). More importantly, <a href="/pcsubstance/?term=ML356[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML356</a>, is active in a cellular based assay and has the ability to block cellular fatty acid biosynthesis. <a href="/pcsubstance/?term=ML356[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML356</a> is chemically stable and will serve as a unique biochemical probe.</p><p>This compound will be particularly valuable to the cancer biology, obesity research, and metabolism communities, as the biochemical and cellular processes that control FAS can now be further explored by pharmacologic inhibition. The original goal for this project was to screen for <i>reversible</i> antagonists of the thioesterase domain of FAS that will prevent cellular fatty acid biosynthesis, selectively induce tumor cell apoptosis, and be useful in treating tumors. We have identified a compound, <a href="/pcsubstance/?term=ML356[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML356</a> that could potentially meet our goals.</p><div id="ml356.s18"><h4>Evidence of selectivity for FAS over other human thioesterases</h4><p>Studies were conducted to determine the selectivity of <a href="/pcsubstance/?term=ML356[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML356</a> for FAS over other human thioesterases. Thioesterases are members of the serine hydrolase family, which also includes a number of other types of enzymes including proteases, dipeptidyl peptidases, epoxide hydrolases etc. To help assess the selectivity of <a href="/pcsubstance/?term=ML356[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML356</a> we used in an activity-based probe polyethyleneglycol-6-carboxytetra-methyl-rhodamine (FP-PEG-TAMRA) that binds covalently to the catalytic serine of all serine hydrolases [<a class="bk_pop" href="#ml356.r47">47</a>]. These studies were done by assessing the ability of <a href="/pcsubstance/?term=ML356[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML356</a> to compete for the binding of the activity-based probe in whole cell lysates. Several analogs of probe <a href="/pcsubstance/?term=ML356[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML356</a> were tested in this assay using lysates of the prostate tumor line (PC3), which expresses FAS, along with numerous other serine hydrolases [<a class="bk_pop" href="#ml356.r48">48</a>]. The PC-3 lysate was incubated with 8 different FAS inhibitors from the screen, including <a href="/pcsubstance/?term=ML356[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML356</a> (<a class="figpopup" href="/books/NBK189923/figure/ml356.f18/?report=objectonly" target="object" rid-figpopup="figml356f18" rid-ob="figobml356f18">Figure 9</a><b>, lane 3 both gels</b>). Then the activity-based probe (FP-PEG-TAMRA) was added to each sample to label the serine hydrolases in the lysate. Samples were resolved by 10% SDS-PAGE and activity-based labeling was visualized at 535 nm. The probe <a href="/pcsubstance/?term=ML356[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML356</a> (<a class="figpopup" href="/books/NBK189923/figure/ml356.f18/?report=objectonly" target="object" rid-figpopup="figml356f18" rid-ob="figobml356f18">Figure 9</a>, #3:CID1811788, MLS-0472190) and an active analog (<a class="figpopup" href="/books/NBK189923/figure/ml356.f18/?report=objectonly" target="object" rid-figpopup="figml356f18" rid-ob="figobml356f18">Figure 9</a>, #2: MLS-0380827) showed inhibition of FAS, whereas an inactive control compound (<a class="figpopup" href="/books/NBK189923/figure/ml356.f18/?report=objectonly" target="object" rid-figpopup="figml356f18" rid-ob="figobml356f18">Figure 9</a>, #1: MLS-0472100) did not. These results show that the probe <a href="/pcsubstance/?term=ML356[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML356</a> and key analogs from the screen block the binding of FP-TAMRA to FAS. However, there is no competition for activity based labeling against any of the other serine hydrolases in the lysate. These findings indicate that <a href="/pcsubstance/?term=ML356[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML356</a> is <i>highly selective</i> for the thioesterase domain of FAS.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml356f18" co-legend-rid="figlgndml356f18"><a href="/books/NBK189923/figure/ml356.f18/?report=objectonly" target="object" title="Figure 9" class="img_link icnblk_img figpopup" rid-figpopup="figml356f18" rid-ob="figobml356f18"><img class="small-thumb" src="/books/NBK189923/bin/ml356f17.gif" src-large="/books/NBK189923/bin/ml356f17.jpg" alt="Figure 9. Inhibition of FAS in PC-3 cells." /></a><div class="icnblk_cntnt" id="figlgndml356f18"><h4 id="ml356.f18"><a href="/books/NBK189923/figure/ml356.f18/?report=objectonly" target="object" rid-ob="figobml356f18">Figure 9</a></h4><p class="float-caption no_bottom_margin">Inhibition of FAS in PC-3 cells. The ability of compounds to bind the FAS holoenzyme was tested by assessing their ability to compete for the binding of an activity-based probe (FP-PEG-TAMRA) that covalently attaches to the active site of the FAS thioesterase. <a href="/books/NBK189923/figure/ml356.f18/?report=objectonly" target="object" rid-ob="figobml356f18">(more...)</a></p></div></div><p>Additional, studies were done to test the selectivity of <a href="/pcsubstance/?term=ML356[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML356</a> for the FAS thioesterase over its most closely related human homolog and enzyme called ACOT4 (<a class="figpopup" href="/books/NBK189923/figure/ml356.f19/?report=objectonly" target="object" rid-figpopup="figml356f19" rid-ob="figobml356f19">Figure 10</a>). Recombinant forms of each enzyme were incubated with <a href="/pcsubstance/?term=ML356[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML356</a> [CID 70680643], and some other analogues of this compound. FP-TAMRA was included in this mixture to label the active site of the FAS thioesterase and ACOT4. <a href="/pcsubstance/?term=ML356[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML356</a> and its active analogs blocked the binding of FP-TAMRA to the active site of the FAS thioesterase but were without effect on activity labeling of ACOT4 (<a class="figpopup" href="/books/NBK189923/figure/ml356.f19/?report=objectonly" target="object" rid-figpopup="figml356f19" rid-ob="figobml356f19">Figure 10A</a>). These findings further attest to the high degree of selectivity of <a href="/pcsubstance/?term=ML356[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML356</a> for the FAS thioesterase.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml356f19" co-legend-rid="figlgndml356f19"><a href="/books/NBK189923/figure/ml356.f19/?report=objectonly" target="object" title="Figure 10" class="img_link icnblk_img figpopup" rid-figpopup="figml356f19" rid-ob="figobml356f19"><img class="small-thumb" src="/books/NBK189923/bin/ml356f18.gif" src-large="/books/NBK189923/bin/ml356f18.jpg" alt="Figure 10. A selection of inhibitors shows selectivity for recombinant FAS-TE and ACOT4." /></a><div class="icnblk_cntnt" id="figlgndml356f19"><h4 id="ml356.f19"><a href="/books/NBK189923/figure/ml356.f19/?report=objectonly" target="object" rid-ob="figobml356f19">Figure 10</a></h4><p class="float-caption no_bottom_margin">A selection of inhibitors shows selectivity for recombinant FAS-TE and ACOT4. Panel A shows the raw data obtained from a fluorescence reading of and SDS-gel. Panel B shows quantification of results in Panel A. MLS-0472100 had no activity in the enzyme-based <a href="/books/NBK189923/figure/ml356.f19/?report=objectonly" target="object" rid-ob="figobml356f19">(more...)</a></p></div></div><p>At this juncture the probes have most of the biochemical properties that we set out to identify; reasonable potency against the recombinant thioesterase, the ability to block the active site of the thioesterase in the context of the FAS holoenzyme, the ability to block fatty acid biosynthesis in whole cells, and selectivity against the most closely related human thioesterase, ACOT4. Together these properties provide the rationale for engaging in a medicinal chemistry effort to optimize potency, retain selectivity, and to improve the pharmacologic properties of the compound so that it has a pharmacokinetic profile suitable for use in long-term animal studies. This medicinal chemistry effort has already begun in the laboratories of the PI and Co-PI. Our objective is to use the optimized probes to study tumor metabolism and tumor growth.</p></div></div></div><div id="ml356.s19"><h2 id="_ml356_s19_">5. References</h2><dl class="temp-labeled-list"><dt>1.</dt><dd><div class="bk_ref" id="ml356.r1">Shurbaji MS, Kuhajda FP, Pasternack GR, Thurmond TS. Expression of oncogenic antigen 519 (OA-519) in prostate cancer is a potential prognostic indicator. <span><span class="ref-journal">Am J Clin Pathol. </span>1992;<span class="ref-vol">97</span>(5):686–691.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/1374214" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 1374214</span></a>]</div></dd><dt>2.</dt><dd><div class="bk_ref" id="ml356.r2">Kuhajda FP, Jenner K, Wood FD, Hennigar RA, Jacobs LB, Dick JD, Pasternack GR. Fatty acid synthesis: a potential selective target for antineoplastic therapy. <span><span class="ref-journal">Proc Natl Acad Sci U S A. </span>1994;<span class="ref-vol">91</span>(14):6379–6383.</span> [<a href="/pmc/articles/PMC44205/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC44205</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/8022791" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8022791</span></a>]</div></dd><dt>3.</dt><dd><div class="bk_ref" id="ml356.r3">Pizer ES, Thupari J, Han WF, Pinn ML, Chrest FJ, Frehywot GL, Townsend CA, Kuhajda FP. Malonyl-coenzyme-A is a potential mediator of cytotoxicity induced by fatty-acid synthase inhibition in human breast cancer cells and xenografts. <span><span class="ref-journal">Cancer Research. </span>2000;<span class="ref-vol">60</span>(2):213–218.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/10667561" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10667561</span></a>]</div></dd><dt>4.</dt><dd><div class="bk_ref" id="ml356.r4">Myers RB, Oelschlager DK, Weiss HL, Frost AR, Grizzle WE. Fatty acid synthase: an early molecular marker of progression of prostatic adenocarcinoma to androgen independence. <span><span class="ref-journal">J Urol. </span>2001;<span class="ref-vol">165</span>(3):1027–1032.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11176534" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11176534</span></a>]</div></dd><dt>5.</dt><dd><div class="bk_ref" id="ml356.r5">Heemers H, Maes B, Foufelle F, Heyns W, Verhoeven G, Swinnen JV. Androgens stimulate lipogenic gene expression in prostate cancer cells by activation of the sterol regulatory element-binding protein cleavage activating protein/sterol regulatory element-binding protein pathway. <span><span class="ref-journal">Mol Endocrinol. </span>2001;<span class="ref-vol">15</span>(10):1817–1828.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11579213" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11579213</span></a>]</div></dd><dt>6.</dt><dd><div class="bk_ref" id="ml356.r6">Bull JH, Ellison G, Patel A, Muir G, Walker M, Underwood M, Khan F, Paskins L. Identification of potential diagnostic markers of prostate cancer and prostatic intraepithelial neoplasia using cDNA microarray. <span><span class="ref-journal">Br J Cancer. </span>2001;<span class="ref-vol">84</span>(11):1512–1519.</span> [<a href="/pmc/articles/PMC2363654/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2363654</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/11384102" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11384102</span></a>]</div></dd><dt>7.</dt><dd><div class="bk_ref" id="ml356.r7">Alo PL, Visca P, Trombetta G, Mangoni A, Lenti L, Monaco S, Botti C, Serpieri DE, Di Tondo U. Fatty acid synthase (FAS) predictive strength in poorly differentiated early breast carcinomas. <span><span class="ref-journal">Tumori. </span>1999;<span class="ref-vol">85</span>(1):35–40.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/10228495" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10228495</span></a>]</div></dd><dt>8.</dt><dd><div class="bk_ref" id="ml356.r8">Alo PL, Visca P, Marci A, Mangoni A, Botti C, Di Tondo U. Expression of fatty acid synthase (FAS) as a predictor of recurrence in stage I breast carcinoma patients. <span><span class="ref-journal">Cancer. </span>1996;<span class="ref-vol">77</span>(3):474–482.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/8630954" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8630954</span></a>]</div></dd><dt>9.</dt><dd><div class="bk_ref" id="ml356.r9">Visca P, Alo PL, Del Nonno F, Botti C, Trombetta G, Marandino F, Filippi S, Di Tondo U, Donnorso RP. 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Practical, catalytic, asymmetric synthesis of beta-lactones via a sequential ketene dimerization/hydrogenation process: inhibitors of the thioesterase domain of fatty acid synthase. <span><span class="ref-journal">J Org Chem. </span>2006;<span class="ref-vol">71</span>(12):4549–4558.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16749788" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16749788</span></a>] [<a href="http://dx.crossref.org/10.1021/jo060392d" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">CrossRef</a>]</div></dd><dt>45.</dt><dd><div class="bk_ref" id="ml356.r45">Wu M, Singh SB, Wang J, Chung CC, Salituro G, Karanam BV, Lee SH, Powles M, Ellsworth KP, Lassman ME, Miller C, Myers RW, Tota MR, Zhang BB, Li C. Antidiabetic and antisteatotic effects of the selective fatty acid synthase (FAS) inhibitor platensimycin in mouse models of diabetes. <span><span class="ref-journal">Proc Natl Acad Sci U S A. </span>2011;<span class="ref-vol">108</span>(13):5378–5383.</span> [<a href="/pmc/articles/PMC3069196/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3069196</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21389266" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21389266</span></a>] [<a href="http://dx.crossref.org/10.1073/pnas.1002588108" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">CrossRef</a>]</div></dd><dt>46.</dt><dd><div class="bk_ref" id="ml356.r46">Singh SB, Jayasuriya H, Ondeyka JG, Herath KB, Zhang C, Zink DL, Tsou NN, Ball RG, Basilio A, Genilloud O, Diez MT, Vicente F, Pelaez F, Young K, Wang J. Isolation, structure, and absolute stereochemistry of platensimycin, a broad spectrum antibiotic discovered using an antisense differential sensitivity strategy. <span><span class="ref-journal">J Am Chem Soc. </span>2006;<span class="ref-vol">128</span>(36):11916–11920.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16953632" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16953632</span></a>] [<a href="http://dx.crossref.org/10.1021/ja062232p" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">CrossRef</a>]</div></dd><dt>47.</dt><dd><div class="bk_ref" id="ml356.r47">Knowles LM, Axelrod F, Browne CD, Smith JW. A fatty acid synthase blockade induces tumor cell-cycle arrest by down-regulating Skp2. <span><span class="ref-journal">J Biol Chem. </span>2004;<span class="ref-vol">279</span>(29):30540–30545.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15138278" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15138278</span></a>] [<a href="http://dx.crossref.org/10.1074/jbc.M405061200" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">CrossRef</a>]</div></dd><dt>48.</dt><dd><div class="bk_ref" id="ml356.r48">Kridel SJ, Axelrod F, Rozenkrantz N, Smith JW. Orlistat is a novel inhibitor of fatty acid synthase with antitumor activity. <span><span class="ref-journal">Cancer Res. </span>2004;<span class="ref-vol">64</span>(6):2070–2075.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15026345" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15026345</span></a>]</div></dd><dt>49.</dt><dd><div class="bk_ref" id="ml356.r49">Schneider CA, Rasband WS, Eliceiri KW. NIH Image to ImageJ: 25 years of image analysis. <span><span class="ref-journal">Nat Methods. </span>2012;<span class="ref-vol">9</span>(7):671–675.</span> [<a href="/pmc/articles/PMC5554542/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5554542</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22930834" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22930834</span></a>]</div></dd></dl></div><div style="display:none"><div style="display:none" id="figml356f4"><img alt="Image ml356f4" src-large="/books/NBK189923/bin/ml356f4.jpg" /></div><div style="display:none" id="figml356f9"><img alt="Image ml356f8" src-large="/books/NBK189923/bin/ml356f8.jpg" /></div><div style="display:none" id="figml356f6"><img alt="Image ml356f5" src-large="/books/NBK189923/bin/ml356f5.jpg" /></div><div style="display:none" id="figml356f7"><img alt="Image ml356f6" src-large="/books/NBK189923/bin/ml356f6.jpg" /></div><div style="display:none" id="figml356f8"><img alt="Image ml356f7" src-large="/books/NBK189923/bin/ml356f7.jpg" /></div></div><div id="bk_toc_contnr"></div></div></div>
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<div xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Views</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="PDF_download" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="/books/NBK189923/?report=reader">PubReader</a></li><li><a href="/books/NBK189923/?report=printable">Print View</a></li><li><a data-jig="ncbidialog" href="#_ncbi_dlg_citbx_NBK189923" data-jigconfig="width:400,modal:true">Cite this Page</a><div id="_ncbi_dlg_citbx_NBK189923" style="display:none" title="Cite this Page"><div class="bk_tt">Ardecky R, Hedrick MP, Gosalia P, et al. Selective inhibitors of FAS-TE. 2013 Apr 12 [Updated 2014 Jan 13]. In: Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010-. <span class="bk_cite_avail"></span></div></div></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="#ml356.s1" ref="log$=inpage&link_id=inpage">Probe Structure & Characteristics</a></li><li><a href="#ml356.s2" ref="log$=inpage&link_id=inpage">Recommendations for Scientific Use of the Probe</a></li><li><a href="#ml356.s3" ref="log$=inpage&link_id=inpage">Materials and Methods</a></li><li><a href="#ml356.s12" ref="log$=inpage&link_id=inpage">Results</a></li><li><a href="#ml356.s16" ref="log$=inpage&link_id=inpage">Discussion</a></li><li><a href="#ml356.s19" ref="log$=inpage&link_id=inpage">References</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Related information</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="discovery_db_links" id="Shutter"></a></div><div class="portlet_content"><ul><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pmc&DbFrom=books&Cmd=Link&LinkName=books_pmc_refs&IdsFromResult=3074720" ref="log$=recordlinks">PMC</a><div class="brieflinkpop offscreen_noflow">PubMed Central citations</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pcassay&DbFrom=books&Cmd=Link&LinkName=books_pcassay_probe&IdsFromResult=3074720" ref="log$=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=3074720" ref="log$=recordlinks">PubChem Substance</a><div class="brieflinkpop offscreen_noflow">Related PubChem Substances</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pubmed&DbFrom=books&Cmd=Link&LinkName=books_pubmed_refs&IdsFromResult=3074720" ref="log$=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/14767544" ref="ordinalpos=1&linkpos=1&log$=relatedarticles&logdbfrom=pubmed">Novel signaling molecules implicated in tumor-associated fatty acid synthase-dependent breast cancer cell proliferation and survival: Role of exogenous dietary fatty acids, p53-p21WAF1/CIP1, ERK1/2 MAPK, p27KIP1, BRCA1, and NF-kappaB.</a><span class="source">[Int J Oncol. 2004]</span><div class="brieflinkpop offscreen_noflow">Novel signaling molecules implicated in tumor-associated fatty acid synthase-dependent breast cancer cell proliferation and survival: Role of exogenous dietary fatty acids, p53-p21WAF1/CIP1, ERK1/2 MAPK, p27KIP1, BRCA1, and NF-kappaB.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Menendez JA, Mehmi I, Atlas E, Colomer R, Lupu R. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">Int J Oncol. 2004 Mar; 24(3):591-608. </em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/29161996" ref="ordinalpos=1&linkpos=2&log$=relatedarticles&logdbfrom=pubmed">Computational screening of fatty acid synthase inhibitors against thioesterase domain.</a><span class="source">[J Biomol Struct Dyn. 2018]</span><div class="brieflinkpop offscreen_noflow">Computational screening of fatty acid synthase inhibitors against thioesterase domain.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Panman W, Nutho B, Chamni S, Dokmaisrijan S, Kungwan N, Rungrotmongkol T. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">J Biomol Struct Dyn. 2018 Nov; 36(15):4114-4125. Epub 2017 Dec 7.</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/15726818" ref="ordinalpos=1&linkpos=3&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Structure and function of animal fatty acid synthase.</a><span class="source">[Lipids. 2004]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Structure and function of animal fatty acid synthase.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Chirala SS, Wakil SJ. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">Lipids. 2004 Nov; 39(11):1045-53. </em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/9047334" ref="ordinalpos=1&linkpos=4&log$=relatedarticles&logdbfrom=pubmed">Mapping of functional interactions between domains of the animal fatty acid synthase by mutant complementation in vitro.</a><span class="source">[Biochemistry. 1997]</span><div class="brieflinkpop offscreen_noflow">Mapping of functional interactions between domains of the animal fatty acid synthase by mutant complementation in vitro.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Joshi AK, Witkowski A, Smith S. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">Biochemistry. 1997 Feb 25; 36(8):2316-22. </em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/15577743" ref="ordinalpos=1&linkpos=5&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> Fatty acid synthase-catalyzed de novo fatty acid biosynthesis: from anabolic-energy-storage pathway in normal tissues to jack-of-all-trades in cancer cells.</a><span class="source">[Arch Immunol Ther Exp (Warsz)....]</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> Fatty acid synthase-catalyzed de novo fatty acid biosynthesis: from anabolic-energy-storage pathway in normal tissues to jack-of-all-trades in cancer cells.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Menendez JA, Lupu R. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">Arch Immunol Ther Exp (Warsz). 2004 Nov-Dec; 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