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<script type="text/javascript" src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.boots.min.js"> </script><title>Allosteric Small Molecule Inhibitors of LMPTP - Probe Reports from the NIH Molecular Libraries Program - NCBI Bookshelf</title>
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<meta name="citation_inbook_title" content="Probe Reports from the NIH Molecular Libraries Program [Internet]">
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<meta name="citation_title" content="Allosteric Small Molecule Inhibitors of LMPTP">
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<meta name="citation_date" content="2015/01/16">
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<meta name="citation_author" content="Robert J. Ardecky">
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<meta name="citation_author" content="Michael P. Hedrick">
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<meta name="citation_author" content="Matthew R. Bliss">
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<meta name="citation_author" content="Nikki Barron">
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<meta name="citation_author" content="Qing Sun">
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<meta name="citation_author" content="Santhi Ganji">
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<meta name="citation_author" content="Alka Mehta">
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<meta name="citation_author" content="Elliot Sugarman">
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<meta name="citation_author" content="Eigo Suyama">
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<meta name="citation_author" content="Layton H. Smith">
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<meta name="citation_author" content="Eduard Sergienko">
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<meta name="citation_author" content="Thomas D.Y. Chung">
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<meta name="citation_author" content="Anthony B. Pinkerton">
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<meta name="citation_author" content="Nunzio Bottini">
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<meta name="citation_pmid" content="25834896">
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<meta name="DC.Title" content="Allosteric Small Molecule Inhibitors of LMPTP">
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<meta name="DC.Publisher" content="National Center for Biotechnology Information (US)">
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<meta name="DC.Contributor" content="Robert J. Ardecky">
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<meta name="DC.Contributor" content="Michael P. Hedrick">
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<meta name="DC.Contributor" content="Stephanie M. Stanford">
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<meta name="DC.Contributor" content="Matthew R. Bliss">
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<meta name="DC.Contributor" content="Jiwen Zou">
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<meta name="DC.Contributor" content="Palak Gosalia">
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<meta name="DC.Contributor" content="Fusayo Yamamoto">
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<meta name="DC.Contributor" content="Monika Milewski">
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<meta name="DC.Contributor" content="Nikki Barron">
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<meta name="DC.Contributor" content="Qing Sun">
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<meta name="DC.Contributor" content="Santhi Ganji">
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<meta name="DC.Contributor" content="Alka Mehta">
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<meta name="DC.Contributor" content="Elliot Sugarman">
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<meta name="DC.Contributor" content="Kevin Nguyen">
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<meta name="DC.Contributor" content="Stefan Vasile">
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<meta name="DC.Contributor" content="Eigo Suyama">
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<meta name="DC.Contributor" content="Arianna Mangravita-Novo">
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<meta name="DC.Contributor" content="Sumeet Salaniwal">
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<meta name="DC.Contributor" content="Paul Kung">
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<meta name="DC.Contributor" content="Layton H. Smith">
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<meta name="DC.Contributor" content="Eduard Sergienko">
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<meta name="DC.Contributor" content="Thomas D.Y. Chung">
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<meta name="DC.Contributor" content="Anthony B. Pinkerton">
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<meta name="DC.Contributor" content="Nunzio Bottini">
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<meta name="DC.Date" content="2015/01/16">
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<meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK280042/">
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<meta name="description" content="Obesity is frequently complicated by a constellation of metabolic and cardiovascular anomalies, called the metabolic syndrome, which significantly increases morbidity and mortality of affected individuals. Insulin resistance is an important component of the metabolic syndrome. Protein tyrosine phosphatases (PTPs) that regulate insulin signaling are in principle excellent therapeutic targets for insulin resistance syndromes. The low molecular weight protein tyrosine phosphatase (LMPTP), encoded by the ACP1 gene, represents an attractive target in this family. LMPTP is highly expressed in adipocytes and there is strong in vitro and in vivo evidence that LMPTP is a negative regulator of insulin signaling and a promising drug target for obesity. Genetic association studies in humans support a role for LMPTP in insulin resistance and the metabolic complications of obesity. In vivo, partial knock-down of LMPTP expression by specific antisense oligonucleotides (ASOs) led to improved glycemic and lipid profiles and decreased insulin resistance in diet-induced obese C57BL/6 mice. This probe report describes the first (and first-in-class) selective allosteric LMPTP inhibitor, ML400 (CID 73050863, SID 173019983). ML400 is potent (EC50∼1μM), selective against other phosphatases, and displays good cell-based activity as well as rodent pharmacokinetics. As such it should be a valuable tool to explore the effects of selective LMPTP inhibition in vitro and in vivo.">
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<meta name="og:title" content="Allosteric Small Molecule Inhibitors of LMPTP">
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<meta name="og:description" content="Obesity is frequently complicated by a constellation of metabolic and cardiovascular anomalies, called the metabolic syndrome, which significantly increases morbidity and mortality of affected individuals. Insulin resistance is an important component of the metabolic syndrome. Protein tyrosine phosphatases (PTPs) that regulate insulin signaling are in principle excellent therapeutic targets for insulin resistance syndromes. The low molecular weight protein tyrosine phosphatase (LMPTP), encoded by the ACP1 gene, represents an attractive target in this family. LMPTP is highly expressed in adipocytes and there is strong in vitro and in vivo evidence that LMPTP is a negative regulator of insulin signaling and a promising drug target for obesity. Genetic association studies in humans support a role for LMPTP in insulin resistance and the metabolic complications of obesity. In vivo, partial knock-down of LMPTP expression by specific antisense oligonucleotides (ASOs) led to improved glycemic and lipid profiles and decreased insulin resistance in diet-induced obese C57BL/6 mice. This probe report describes the first (and first-in-class) selective allosteric LMPTP inhibitor, ML400 (CID 73050863, SID 173019983). ML400 is potent (EC50∼1μM), selective against other phosphatases, and displays good cell-based activity as well as rodent pharmacokinetics. As such it should be a valuable tool to explore the effects of selective LMPTP inhibition in vitro and in vivo.">
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match">◀</a><button id="jr-fip-matches">no matches yet</button><a id="jr-fip-next" class="wsprkl btn" title="Jump to next match">▶</a></nav></nav></div><div id="jr-epub-interstitial" class="hidden"></div><div id="jr-content"><article data-type="main"><div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><div class="fm-sec"><h1 id="_NBK280042_"><span class="title" itemprop="name">Allosteric Small Molecule Inhibitors of LMPTP</span></h1><p class="contribs">Ardecky RJ, Hedrick MP, Stanford SM, et al.</p><p class="fm-aai"><a href="#_NBK280042_pubdet_">Publication Details</a></p></div></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="_abs_rndgid_" itemprop="description"><p>Obesity is frequently complicated by a constellation of metabolic and cardiovascular anomalies<b>,</b> called the metabolic syndrome, which significantly increases morbidity and mortality of affected individuals. Insulin resistance is an important component of the metabolic syndrome. Protein tyrosine phosphatases (PTPs) that regulate insulin signaling are in principle excellent therapeutic targets for insulin resistance syndromes. The low molecular weight protein tyrosine phosphatase (LMPTP), encoded by the <i>ACP1</i> gene, represents an attractive target in this family. LMPTP is highly expressed in adipocytes and there is strong <i>in vitro</i> and <i>in vivo</i> evidence that LMPTP is a negative regulator of insulin signaling and a promising drug target for obesity. Genetic association studies in humans support a role for LMPTP in insulin resistance and the metabolic complications of obesity. <i>In vivo</i>, partial knock-down of LMPTP expression by specific antisense oligonucleotides (ASOs) led to improved glycemic and lipid profiles and decreased insulin resistance in diet-induced obese C57BL/6 mice. This probe report describes the first (and first-in-class) selective allosteric LMPTP inhibitor, <a href="/pcsubstance/?term=ML400[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML400</a> (CID 73050863, <a href="https://pubchem.ncbi.nlm.nih.gov/substance/173019983" ref="pagearea=abstract&targetsite=entrez&targetcat=link&targettype=pubchem">SID 173019983</a>). <a href="/pcsubstance/?term=ML400[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML400</a> is potent (EC<sub>50</sub>∼1μM), selective against other phosphatases, and displays good cell-based activity as well as rodent pharmacokinetics. As such it should be a valuable tool to explore the effects of selective LMPTP inhibition <i>in vitro</i> and <i>in vivo</i>.</p></div><div class="h2"></div><p><b>Assigned Assay Grant #:</b> 1 R03 DA033986-01 (Cycle 19)</p><p><b>Screening Center Name & PI:</b> Sanford-Burnham Medical Research Institute & <i>Michael R. Jackson, Ph.D.</i></p><p><b>Chemistry Center Name & PI:</b> Sanford-Burnham Medical Research Institute & <i>Michael R. Jackson, Ph.D.</i></p><p><b>Assay Submitter & Institution:</b> Nunzio Bottini, M.D., Ph.D., LIAI, La Jolla, CA</p><p><b>PubChem Summary Bioassay Identifier (AID):</b>
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<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/651562" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">651562</a></p><div id="ml400.s1"><h2 id="_ml400_s1_">Probe Structure & Characteristics</h2><p>This Center Probe Report describes <a href="/pcsubstance/?term=ML400[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML400</a>, a selective allosteric inhibitor of LMPTP. <a href="/pcsubstance/?term=ML400[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML400</a> has a central quinazoline core. The chemical structure and data summary are shown in (<a class="figpopup" href="/books/NBK280042/table/ml400.t1/?report=objectonly" target="object" rid-figpopup="figml400t1" rid-ob="figobml400t1">Table 1</a>)</p><div id="ml400.f1" class="figure bk_fig"><div class="graphic"><img src="/books/NBK280042/bin/ml400f1.jpg" alt="Chemical Structure of ML400." /></div><h3><span class="title">Chemical Structure of ML400</span></h3></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml400t1"><a href="/books/NBK280042/table/ml400.t1/?report=objectonly" target="object" title="Table 1" class="img_link icnblk_img figpopup" rid-figpopup="figml400t1" rid-ob="figobml400t1"><img class="small-thumb" src="/books/NBK280042/table/ml400.t1/?report=thumb" src-large="/books/NBK280042/table/ml400.t1/?report=previmg" alt="Table 1. Potency and selectivity characteristics for probe ML400." /></a><div class="icnblk_cntnt"><h4 id="ml400.t1"><a href="/books/NBK280042/table/ml400.t1/?report=objectonly" target="object" rid-ob="figobml400t1">Table 1</a></h4><p class="float-caption no_bottom_margin">Potency and selectivity characteristics for probe ML400. </p></div></div></div><div id="ml400.s2"><h2 id="_ml400_s2_">1. Recommendations for Scientific Use of the Probe</h2><p><b>Background:</b> Obesity is frequently complicated by a constellation of metabolic and cardiovascular anomalies<b>,</b> called the metabolic syndrome, which significantly increases morbidity and mortality of affected individuals<a class="bibr" href="#ml400.r1" rid="ml400.r1">1</a>. Insulin resistance is an important component of the metabolic syndrome. Protein tyrosine phosphatases (PTPs) that regulate insulin signaling are in principle excellent therapeutic targets for insulin resistance syndromes<a class="bibr" href="#ml400.r2" rid="ml400.r2">2</a>. Indeed, PTP1B, a critical negative regulator of insulin signaling in liver and skeletal muscle, is currently an important drug target in obesity and type2 diabetes. We focus herein on another PTP, the low molecular weight protein tyrosine phosphatase (LMPTP), encoded by the <i>ACP1</i> gene. LMPTP is highly expressed in adipocytes<a class="bibr" href="#ml400.r3" rid="ml400.r3">3</a>. <b>There is strong <i>in vitro</i> and <i>in vivo</i> evidence that LMPTP is a negative regulator of insulin signaling and a promising drug target in obesity</b>. Genetic association studies in humans support a negative role for LMPTP in insulin resistance and the metabolic complications of obesity<a class="bibr" href="#ml400.r4" rid="ml400.r4">4</a>. <i>In vivo</i>, partial knock-down of LMPTP expression by specific antisense oligonucleotides (ASOs) led to improved glycemic and lipid profiles and decreased insulin resistance in diet-induced obese C57BL/6 mice<a class="bibr" href="#ml400.r5" rid="ml400.r5">5</a>. Interestingly, anti-LMPTP ASOs did not induce any metabolic phenotype in lean mice. Our current working model is that LMPTP plays a critical negative role in adipocyte insulin signaling<a class="bibr" href="#ml400.r6" rid="ml400.r6">6</a>, while it is less important in liver and muscle, where it can be at least partially compensated for by PTP1B and/or other prominent PTPs. <b>We hypothesize that a specific small-molecule inhibitor of LMPTP will significantly reduce obesity associated insulin resistance and decrease the severity of the metabolic syndrome in obesity.</b> One important and innovative aspect of our screening effort was that <b>we screened for non-competitive allosteric inhibitors</b>. Searches for active site competitive inhibitors of PTPs by HTS are notoriously plagued by problems with low selectivity and lack of cell-permeability of the identified hits<a class="bibr" href="#ml400.r7" rid="ml400.r7">7</a>. Although several prominent experts have hypothesized that non active site allosteric inhibitors could be the solution to the above-mentioned problem, there is still a considerable paucity of publications in this field<a class="bibr" href="#ml400.r8" rid="ml400.r8">8</a>. Currently only three allosteric inhibitors of PTPs have been published<a class="bibr" href="#ml400.r9" rid="ml400.r9">9</a>-<a class="bibr" href="#ml400.r11" rid="ml400.r11">11</a>, and <b>there is no known allosteric inhibitor of LMPTP</b>.</p><p><b>Obesity and the metabolic syndrome.</b> It has been estimated that every year in the U.S. more than 70 billion dollars are spent for the treatment of obesity-related conditions<a class="bibr" href="#ml400.r12" rid="ml400.r12">12</a> and almost 300,000 deaths/year can be attributed to the complications of obesity<a class="bibr" href="#ml400.r13" rid="ml400.r13">13</a>. Obese patients often show multiple metabolic and cardiovascular anomalies known as “the metabolic syndrome”, including glucose intolerance, hyperlipidemia (especially high triglycerides with low HDL), and hypertension<a class="bibr" href="#ml400.r1" rid="ml400.r1">1</a>. New pharmacologic approaches to correct the metabolic syndrome in obese individuals are urgently needed.</p><p><b>Promise and problems of PTPs as drug targets for the metabolic syndrome.</b> Obesity-induced insulin resistance is believed to be a central pathogenic factor in the metabolic syndrome<a class="bibr" href="#ml400.r14" rid="ml400.r14">14</a>. Obese patients are routinely treated with oral hypoglycemic agents, however even combinations of multiple agents are often insufficient to ensure adequate glycemic control, requiring the addition of parenteral insulin to the regimen. Reduced signal transduction at several levels after engagement of the insulin receptor (IR) has been observed in multiple insulin resistance syndromes, including the metabolic syndrome<a class="bibr" href="#ml400.r15" rid="ml400.r15">15</a>, <a class="bibr" href="#ml400.r16" rid="ml400.r16">16</a>. The IR is a protein tyrosine kinase, and tyrosine phosphorylation plays an important role in insulin signal transduction. Pharmacological treatments able to increase the activity of the IR and/or tyrosine phosphorylation of IR targets are currently viewed as promising ways to reduce insulin resistance<a class="bibr" href="#ml400.r17" rid="ml400.r17">17</a>. Several PTPs are involved in the regulation of insulin signaling<a class="bibr" href="#ml400.r18" rid="ml400.r18">18</a>,<a class="bibr" href="#ml400.r19" rid="ml400.r19">19</a>. In 1999 the Kennedy group reported compelling evidence that the tyrosine phosphatase PTP1B is an important <i>in vivo</i> inhibitor of insulin signaling. Mice carrying a deletion of PTP1B showed reduced obesity and insulin resistance while lacking major side effects<a class="bibr" href="#ml400.r20" rid="ml400.r20">20</a>. This seminal paper triggered a major search for pharmacological inhibitors of PTP1B<a class="bibr" href="#ml400.r2" rid="ml400.r2">2</a>,<a class="bibr" href="#ml400.r21" rid="ml400.r21">21</a>. In addition to PTP1B, several other PTPs are now known to downregulate insulin signaling <i>in vivo</i> and are considered good pharmacological targets for insulin resistance<a class="bibr" href="#ml400.r22" rid="ml400.r22">22</a>. Anti-PTP agents are envisioned as a possible new class or hypoglycemic agents and in principle could be combined with currently available oral antidiabetic medications. Due to their mechanism of action on the IR, they also could in principle act as potent insulin-sparing agents when used in combination with parenteral insulin. Although PTPs are good targets for insulin resistance and other human diseases, drugging this family of enzymes is considered a difficult task<a class="bibr" href="#ml400.r7" rid="ml400.r7">7</a>. Searches for active-site competitive inhibitors of PTPs are plagued by problems with <u><i>low selectivity</i></u> and <u><i>lack of cell-permeability</i></u> of the hits. These problems stem in part from the particular features of the PTPs active site, which is small, well conserved among different members of the family, and highly charged<a class="bibr" href="#ml400.r7" rid="ml400.r7">7</a> as it has evolved to bind and “recognize” the phosphate moiety of phosphorylated proteins. Several experts have hypothesized that targeting secondary allosteric sites could be a solution to these three above-mentioned problems<a class="bibr" href="#ml400.r8" rid="ml400.r8">8</a>. The first allosteric inhibitor of PTP1B was published in 2004 by Sunesis, Inc.<a class="bibr" href="#ml400.r9" rid="ml400.r9">9</a>. This uncharged compound does not bind to the highly charged active site and is promising, since it shows superior selectivity properties and is active in cell-based assays. However, this is a very new field, and there is still a considerable paucity of publications. One additional allosteric inhibitor of PTP1B has been reported<a class="bibr" href="#ml400.r10" rid="ml400.r10">10</a>, and we recently published an allosteric inhibitor series for PTPN22<a class="bibr" href="#ml400.r11" rid="ml400.r11">11</a>, and both compounds were active in cell-based assays. There is no known allosteric inhibitor of any other PTP, including LMPTP.</p><p><b>LMPTP: a novel drug target for the metabolic syndrome.</b> This grant proposal focuses on the low molecular weight PTP, a class II PTP<a class="bibr" href="#ml400.r23" rid="ml400.r23">23</a>, encoded by the gene <i>ACP1</i>. LMPTP is a small (18 kD) cytosolic enzyme that is expressed ubiquitously but has particularly high expression in adipocytes<a class="bibr" href="#ml400.r3" rid="ml400.r3">3</a>,<a class="bibr" href="#ml400.r24" rid="ml400.r24">24</a>. As a result of an alternative mRNA splicing mechanism, LMPTP is usually found as two isozymes, called LMPTP-A and –B (the rodent isoforms are called respectively LMPTP-IF1 and -IF2)<a class="bibr" href="#ml400.r25" rid="ml400.r25">25</a>,<a class="bibr" href="#ml400.r26" rid="ml400.r26">26</a>. In humans the total enzymatic activity of LMPTP is variable and is determined by a common genetic polymorphism<a class="bibr" href="#ml400.r27" rid="ml400.r27">27</a>. This unique feature makes it possible to test the involvement of LMPTP in human diseases by genetic association studies (for a review of associations between LMPTP and human diseases see ref. <a class="bibr" href="#ml400.r28" rid="ml400.r28">28</a>). Several studies have shown that LMPTP is an inhibitor of insulin signaling. In cell lines LMPTP is able to inhibit both the metabolic and growth-inducing effects of insulin<a class="bibr" href="#ml400.r29" rid="ml400.r29">29</a>. Also <i>in vitro</i> the phosphatase dephosphorylates peptides derived from the phosphorylated IGF-1 receptor and IR<a class="bibr" href="#ml400.r30" rid="ml400.r30">30</a>. Increased insulin signaling was observed in the adipose tissue of obese mice treated with anti-LMPTP antisense oligonucleotides (ASO). In the same study LMPTP was also easily co-precipitated with the IR. Multiple lines of evidence suggest that LMPTP plays an important role in the metabolic syndrome. The first line of evidence comes from human genetic studies. The <i>ACP1</i> gene is located in one of the candidate genome regions for obesity on chromosome 2p25 and is currently included in the obesity gene map<a class="bibr" href="#ml400.r31" rid="ml400.r31">31</a>. We and others carried out several genetic studies in obesity and type 2 diabetes. These studies showed that carriers of <i>ACP1</i> alleles associated with low enzymatic activity tend to have lower non-fasting glucose levels and are protected from obesity-associated lipid anomalies<a class="bibr" href="#ml400.r4" rid="ml400.r4">4</a>,<a class="bibr" href="#ml400.r32" rid="ml400.r32">32</a>-<a class="bibr" href="#ml400.r34" rid="ml400.r34">34</a>. Strong <i>in vivo</i> evidence suggesting that inhibition of LMPTP decreases the insulin resistance associated with obesity has been obtained recently at Isis Pharmaceuticals Inc., by treating mice with anti-LMPTP ASOs<a class="bibr" href="#ml400.r5" rid="ml400.r5">5</a>. Leptin-deficient or diet-induced obese mice treated with specific anti-LMPTP ASOs showed a marked improvement of lipid profiles, and of glucose and insulin tolerance, in the absence of significant side effects<a class="bibr" href="#ml400.r5" rid="ml400.r5">5</a>. These data strongly suggest that LMPTP is a promising pharmacological target for obesity-associated metabolic syndrome. Active site inhibitors of the LMPTP are under development in several laboratories<a class="bibr" href="#ml400.r35" rid="ml400.r35">35</a>. The Ottaná group reported 5-arylidene-2,4-thiazolidinediones as a novel inhibitor class for PTPs, including LMPTP<a class="bibr" href="#ml400.r36" rid="ml400.r36">36</a>-<a class="bibr" href="#ml400.r38" rid="ml400.r38">38</a>. More recently Forghieri <i>et al.</i> reported the synthesis of flavonoid derivatives, which inhibited LMPTP and PTP1B and showed activity in cell-based assays of insulin signaling<a class="bibr" href="#ml400.r39" rid="ml400.r39">39</a>. Although these studies show that there is a high level of interest in LMPTP, so far all the published LMPTP inhibitors have been obtained using conventional approaches, and they have low potential to yield leads with good drug-like properties. Although there are no known allosteric inhibitors of LMPTP, it has been reported that hypoxanthine is an allosteric stimulator of LMPTP-A, strongly suggesting that the enzyme has at least one allosteric site<a class="bibr" href="#ml400.r40" rid="ml400.r40">40</a>.</p><p><b><u>Prior Art:</u></b> A comprehensive review of all of the published LMPTP compounds is available<a class="bibr" href="#ml400.r41" rid="ml400.r41">41</a>. <i>All of these are competitive inhibitors w/ limited selectivity or cell permeability, or non-competitive but of poor potency with no selectivity of cell-activity data</i>. Additionally, a series of benzoic acid derivatives that inhibited by a competitive mechanism both PTP1B and LMPTP-A has been reported.<a class="bibr" href="#ml400.r42" rid="ml400.r42">42</a> Treatment of mouse C2C12 skeletal muscle cells with several of these compounds increased tyrosine phosphorylation of the insulin receptor. Lastly, there is a recent report of a series of inhibitors of LMPTP-B that were first identified <i>in silico</i>.<a class="bibr" href="#ml400.r43" rid="ml400.r43">43</a> The compounds were not tested against LMPTP-A, or any other PTP1B, nor were they tested in cell-based assays. An additional SciFinder search was performed on March 20, 2014 and returned no additional relevant references.</p><p><b>Use of Probes.</b> There are no known allosteric inhibitors of LMPTP, the only member of the class II of tyrosine phosphatases. Orthosteric inhibitors are plagued by lack of selectivity against other phosphatases, especially among enzymes belonging the class I of PTPs, as well as lack of cellular efficacy. Our probe displays selectivity against two PTPs that are representative of the two major types of class I phosphatases, Lymphoid Phosphatase isoform 1(LYP-1, a tyrosine-specific phosphatase) and VH1-related (VHR, a dual-specificity phosphatase). Although LMPTP appears to be a promising therapeutic target for metabolic syndrome, the current probes available that inhibit the enzymatic activity of LMPTP are unsuitable for preclinical experimentation in rodent models of disease. <a href="/pcsubstance/?term=ML400[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML400</a> will be used for exploring the effect of selective <i>in vitro</i>, in cell and <i>in vivo</i> inhibition of LMPTP. <i>In vivo</i>, <a href="/pcsubstance/?term=ML400[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML400</a> will be used to test whether acute inhibition of the activity of LMPTP is efficacious in treating metabolic syndrome in diet-induced obese mice. Additionally, a selective, cell-permeable inhibitor of LMPTP will provide an invaluable resource to the tyrosine phosphatase community for studies of LMPTP biology and in the areas of diet-induced obesity and type 2 diabetes therapies.</p><p>Therefore, there still remains an unmet need for novel potent, selective, not competitive, cell-permeable and cell-active LMPTP inhibitors not targeted to the conserved active site of phosphatases.</p></div><div id="ml400.s3"><h2 id="_ml400_s3_">2. Materials and Methods</h2><div id="ml400.s4"><h3>2.1. Assays</h3><p><a class="figpopup" href="/books/NBK280042/table/ml400.t2/?report=objectonly" target="object" rid-figpopup="figml400t2" rid-ob="figobml400t2">Table 2</a> summarizes details for the assays that enabled this probe discovery project. A detailed description of the Primary assay can be found in the PubChem AIDs listed</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml400t2"><a href="/books/NBK280042/table/ml400.t2/?report=objectonly" target="object" title="Table 2" class="img_link icnblk_img figpopup" rid-figpopup="figml400t2" rid-ob="figobml400t2"><img class="small-thumb" src="/books/NBK280042/table/ml400.t2/?report=thumb" src-large="/books/NBK280042/table/ml400.t2/?report=previmg" alt="Table 2. Summary of Assays and AIDs." /></a><div class="icnblk_cntnt"><h4 id="ml400.t2"><a href="/books/NBK280042/table/ml400.t2/?report=objectonly" target="object" rid-ob="figobml400t2">Table 2</a></h4><p class="float-caption no_bottom_margin">Summary of Assays and AIDs. </p></div></div></div><div id="ml400.s5"><h3>2.2. Probe Chemical Characterization</h3><p><b>Chemical name of probe compound.</b> The IUPAC name of the probe is 2-(4-methoxyphenyl)-<i>N</i>-(3-(piperidin-1-yl)propyl)quinazolin-4-amine. The actual batch prepared, tested and submitted to the MLSMR is archived as <a href="https://pubchem.ncbi.nlm.nih.gov/substance/73019983" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 73019983</a> corresponding to CID 73050863. The probe <a href="/pcsubstance/?term=ML400[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML400</a> does not have any chiral centers (<a class="figpopup" href="/books/NBK280042/figure/ml400.f2/?report=objectonly" target="object" rid-figpopup="figml400f2" rid-ob="figobml400f2">Figure 1</a>)</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml400f2" co-legend-rid="figlgndml400f2"><a href="/books/NBK280042/figure/ml400.f2/?report=objectonly" target="object" title="Figure 1" class="img_link icnblk_img figpopup" rid-figpopup="figml400f2" rid-ob="figobml400f2"><img class="small-thumb" src="/books/NBK280042/bin/ml400f2.gif" src-large="/books/NBK280042/bin/ml400f2.jpg" alt="Figure 1. Structure of ML400." /></a><div class="icnblk_cntnt" id="figlgndml400f2"><h4 id="ml400.f2"><a href="/books/NBK280042/figure/ml400.f2/?report=objectonly" target="object" rid-ob="figobml400f2">Figure 1</a></h4><p class="float-caption no_bottom_margin">Structure of ML400. </p></div></div><p><b>Solubility and Stability of <a href="/pcsubstance/?term=ML400[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML400</a> in PBS at room temperature.</b> The stability of <a href="/pcsubstance/?term=ML400[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML400</a> was investigated (<a class="figpopup" href="/books/NBK280042/figure/ml400.f3/?report=objectonly" target="object" rid-figpopup="figml400f3" rid-ob="figobml400f3">Figure 2</a>) in aqueous buffers at room temperature by monitoring the amount of starting <a href="/pcsubstance/?term=ML400[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML400</a> apparently remaining after incubation at room temperature in either PBS (pH 7.4) or 1:1 PBS:acetonitrile (v/v). <a href="/pcsubstance/?term=ML400[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML400</a> was stable in both PBS or PBS:acetonitrile with 100% remaining after 48 hrs. (Fitted curves are not plotted to show that data points are virtually superimposable). As noted in the <i>Summary of in vitro ADME/T properties</i>
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<a href="/pcsubstance/?term=ML400[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML400</a> has excellent solubility (>103 μg/mL, >24.4 μM) at pH 5.0, 6.2 and 7.4 in pION buffer and comparable solubility in PBS at pH 7.4. The scaffold structure represented by <a href="/pcsubstance/?term=ML400[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML400</a> has no substantial chemical liabilities.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml400f3" co-legend-rid="figlgndml400f3"><a href="/books/NBK280042/figure/ml400.f3/?report=objectonly" target="object" title="Figure 2" class="img_link icnblk_img figpopup" rid-figpopup="figml400f3" rid-ob="figobml400f3"><img class="small-thumb" src="/books/NBK280042/bin/ml400f3.gif" src-large="/books/NBK280042/bin/ml400f3.jpg" alt="Figure 2. Stability of ML400 in 1× PBS and 1:1 PBS:ACN at RT." /></a><div class="icnblk_cntnt" id="figlgndml400f3"><h4 id="ml400.f3"><a href="/books/NBK280042/figure/ml400.f3/?report=objectonly" target="object" rid-ob="figobml400f3">Figure 2</a></h4><p class="float-caption no_bottom_margin">Stability of ML400 in 1× PBS and 1:1 PBS:ACN at RT. </p></div></div><p><a class="figpopup" href="/books/NBK280042/table/ml400.t3/?report=objectonly" target="object" rid-figpopup="figml400t3" rid-ob="figobml400t3">Table 3</a> summarizes the deposition of the Probe and 5 analogs.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml400t3"><a href="/books/NBK280042/table/ml400.t3/?report=objectonly" target="object" title="Table 3" class="img_link icnblk_img figpopup" rid-figpopup="figml400t3" rid-ob="figobml400t3"><img class="small-thumb" src="/books/NBK280042/table/ml400.t3/?report=thumb" src-large="/books/NBK280042/table/ml400.t3/?report=previmg" alt="Table 3. Probe and Analog Submissions to MLSMR (Evotec) for Small Molecule Inhibitors of LMPTP." /></a><div class="icnblk_cntnt"><h4 id="ml400.t3"><a href="/books/NBK280042/table/ml400.t3/?report=objectonly" target="object" rid-ob="figobml400t3">Table 3</a></h4><p class="float-caption no_bottom_margin">Probe and Analog Submissions to MLSMR (Evotec) for Small Molecule Inhibitors of LMPTP. </p></div></div></div><div id="ml400.s6"><h3>2.3. Probe Preparation</h3><p>This probe is not commercially available. A 27 mg sample of <a href="/pcsubstance/?term=ML400[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML400</a> synthesized at SBCCG has been deposited in the MLSMR (Evotec) (see Probe Submission <a class="figpopup" href="/books/NBK280042/table/ml400.t4/?report=objectonly" target="object" rid-figpopup="figml400t4" rid-ob="figobml400t4">Table 4</a>). The probe <a href="/pcsubstance/?term=ML400[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML400</a> was readily prepared in 4 steps from commercially available starting materials. (Compounds are numbered as in <a class="figpopup" href="/books/NBK280042/figure/ml400.f4/?report=objectonly" target="object" rid-figpopup="figml400f4" rid-ob="figobml400f4">Scheme 1</a>).</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml400t4"><a href="/books/NBK280042/table/ml400.t4/?report=objectonly" target="object" title="Table 4" class="img_link icnblk_img figpopup" rid-figpopup="figml400t4" rid-ob="figobml400t4"><img class="small-thumb" src="/books/NBK280042/table/ml400.t4/?report=thumb" src-large="/books/NBK280042/table/ml400.t4/?report=previmg" alt="Table 4. Summary of in vitro ADME Properties of selected LMPTP inhibitors." /></a><div class="icnblk_cntnt"><h4 id="ml400.t4"><a href="/books/NBK280042/table/ml400.t4/?report=objectonly" target="object" rid-ob="figobml400t4">Table 4</a></h4><p class="float-caption no_bottom_margin">Summary of <i>in vitro</i> ADME Properties of selected LMPTP inhibitors. </p></div></div><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml400f4" co-legend-rid="figlgndml400f4"><a href="/books/NBK280042/figure/ml400.f4/?report=objectonly" target="object" title="Scheme 1" class="img_link icnblk_img figpopup" rid-figpopup="figml400f4" rid-ob="figobml400f4"><img class="small-thumb" src="/books/NBK280042/bin/ml400f4.gif" src-large="/books/NBK280042/bin/ml400f4.jpg" alt="Scheme 1. Synthesis of ML400, conditions: a. 4-Methoxybenzoyl chloride, DIPEA, DCM, 0°C to RT, overnight (80%); b. t-BuOK, t-BuOH, 75°C, overnight (84%); c. POCl3, 90°C, overnight (61%); d. 3-(Piperidin-1-yl)propan-1-amine, t-BuOK 10%, Dry DMA, 135°C, overnight, nitrogen atmosphere (57%)." /></a><div class="icnblk_cntnt" id="figlgndml400f4"><h4 id="ml400.f4"><a href="/books/NBK280042/figure/ml400.f4/?report=objectonly" target="object" rid-ob="figobml400f4">Scheme 1</a></h4><p class="float-caption no_bottom_margin">Synthesis of ML400, conditions: <i>a.</i> 4-Methoxybenzoyl chloride, DIPEA, DCM, 0°C to RT, overnight (80%); <i>b.</i> t-BuOK, t-BuOH, 75°C, overnight (84%); <i>c.</i> POCl3, 90°C, overnight (61%); <i>d.</i> 3-(Piperidin-1-yl)propan-1-amine, t-BuOK 10%, Dry <a href="/books/NBK280042/figure/ml400.f4/?report=objectonly" target="object" rid-ob="figobml400f4">(more...)</a></p></div></div><div id="ml400.s7"><h4>Preparation of <i>N</i>-(2-acetylphenyl)-4-methoxybenzamide [2]</h4><div id="ml400.f5" class="figure"><div class="graphic"><img src="/books/NBK280042/bin/ml400f5.jpg" alt="Image ml400f5" /></div></div><p>To a solution of 1-(2-aminophenyl)ethanone <b>1</b> (5.0 g, 37 mmol) and DIPEA (13 mL, 74 mmol) in 200 mL of THF in an ice bath was added 4-methoxybenzoyl chloride(7.5 mL, 56 mmol) dropwise. After 30 min at 0°C, the mixture was stirred at room temperature overnight and poured in 50 mL of ice water. The precipitate was collected and washed with water and then methanol. The solid was dried under vacuum to yield 8.0 g of crude product <b>2</b> (80% yield). MS (EI) m/z 270 (M+1).</p></div><div id="ml400.s8"><h4>Preparation of 2-(4-methoxyphenyl)quinolin-4-ol [3]</h4><div id="ml400.f6" class="figure"><div class="graphic"><img src="/books/NBK280042/bin/ml400f6.jpg" alt="Image ml400f6" /></div></div><p><i>N</i>-(2-acetylphenyl)-4-methoxybenzamide <b>2</b> (4.0 g, 15 mmol) was suspended in 100 mL of <i>tert</i>-butyl alcohol. Potassium <i>tert</i>-butoxide (3.3 g, 30 mmol) was added. The mixture was heated at 75°C overnight at nitrogen atmosphere. When the reaction was determined to be complete by HPLC, the reaction mixture was cooled and poured into 50 mL of ice water. 10% aqueous HCl was added until pH=6. The solid was collected and washed several times with water to afford 3.1 g of crude product <b>3</b> (84 % yield). MS (EI) m/z 252 (M+1).</p></div><div id="ml400.s9"><h4>Preparation of 4-chloro-2-(4-methoxyphenyl)quinoline [4]</h4><div id="ml400.f7" class="figure"><div class="graphic"><img src="/books/NBK280042/bin/ml400f7.jpg" alt="Image ml400f7" /></div></div><p>2-(4-methoxyphenyl)quinolin-4-ol <b>3</b> (3.1 g, 12.4 mmol) was added to phosphorus oxychloride POCl<sub>3</sub> (50 mL, 540 mmol) to give an dark solution, then several drops of DMF was added if necessary. The reaction was heated at 90°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 basified with 1N NaOH solution, extracted with ethyl acetate and dried over magnesium sulfate. The organic layer was concentrated under reduced pressure to the crude product, which was chromatographed on silica gel and eluted with ethyl acetate and dichoromethane (0:100 to 30:70 gradient) to yield 2.0 g of product <b>4</b> (61 % yield). <sup>1</sup>H NMR (400 MHz, DMSO-d) δ 3.84 (s, 3H), 7.09 (m, 2H), 7.70 (m, 1H), 7.88 (m, 1H), 8.09 (m, 1H), 8.18 (m, 1H), 8.27 (m, 2H), 8.36 (m, 1H). MS (EI) m/z 270 (M+1).</p></div><div id="ml400.s10"><h4>Preparation of 2-(4-methoxyphenyl)-<i>N</i>-(3-(piperidin-1-yl)propyl)quinolin-4-amine [ML400]</h4><div id="ml400.f8" class="figure bk_fig"><div class="graphic"><img src="/books/NBK280042/bin/ml400f8.jpg" alt="ML400." /></div><h3><span class="title">ML400</span></h3></div><p>Potassium <i>tert</i>-butoxide (50 mg, 0.5 mmol)) was added to a solution of 4-chloro-2-(4-methoxy-phenyl)quinoline <b>4</b> (1.0 g, 3.7 mmol) and 3-(Piperidin-1-yl)propan-1-amine (1.1 g, 7.7 mmol) in dry DMA (50 ml). The reaction was heated at 135°C overnight at nitrogen atmosphere. When the reaction was determined to be complete by HPLC, the reaction mixture was cooled to room temperature and evaporated under vacuum to give a residue. 20 mL of water was added and extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give the crude product, which was subjected to be purified by preparative HPLC to afford 0.8 g of <a href="/pcsubstance/?term=ML400[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML400</a> (57% yield). <sup>1</sup>H NMR (400 MHz, DMSO-d) δ 1.44 (m, 2H), 1.60 (m, 4H), 1.97 (m, 2H), 2.72 (m, 6H), 3.45 (m, 2H), 3.82 (s, 3H), 4.94 (s, 2H), 6.91 (s, 1H), 7.04 (m, 2H), 7.39 (m, 2H), 7.61 (m, 1H), 7 .82 (m, 1H), 8.13 (m, 3H), 8.26 (s, 2H). <sup>13</sup>C NMR (400 MHz, DMSO-d) δ(ppm) 22.8, 23.7, 24.1, 53.0, 55.3, 94.5, 113.8, 117.7, 121.5, 123.6, 128.6, 129.3, 132.0, 147.7, 150.9, 156.0, 160.2, 164.4. MS (EI) m/z 376 (M+1).</p><div id="ml400.f9" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%203.%201H%20NMR%20Spectrum%20of%20ML400%20(400%20MHz%2C%20CDCl3).&p=BOOKS&id=280042_ml400f9.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/NBK280042/bin/ml400f9.jpg" alt="Figure 3. 1H NMR Spectrum of ML400 (400 MHz, CDCl3)." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 3</span><span class="title"><sup>1</sup>H NMR Spectrum of ML400 (400 MHz, CDCl<sub>3</sub>)</span></h3></div><div id="ml400.f10" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%204.%2013C%20NMR%20Spectrum%20of%20ML400%20(125%20MHz%2C%20CDCl3).&p=BOOKS&id=280042_ml400f10.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/NBK280042/bin/ml400f10.jpg" alt="Figure 4. 13C NMR Spectrum of ML400 (125 MHz, CDCl3)." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 4</span><span class="title"><sup>13</sup>C NMR Spectrum of ML400 (125 MHz, CDCl<sub>3</sub>)</span></h3></div><div id="ml400.f11" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%205.%20Composite%20LC%2FMS%20for%20ML400.&p=BOOKS&id=280042_ml400f11.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/NBK280042/bin/ml400f11.jpg" alt="Figure 5. Composite LC/MS for ML400." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 5</span><span class="title">Composite LC/MS for ML400</span></h3></div></div></div></div><div id="ml400.s11"><h2 id="_ml400_s11_">3. Results</h2><div id="ml400.s12"><h3>3.1. Dose Response Curves for Probe</h3><div id="ml400.f12" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%206.%20Dose%20response%20curves%20of%20ML400%20in%20the%20LMPTP%20enzyme%20inhibition%20assays%20with%20OMFP%20and%20pNPP%20as%20substrates%2C%20as%20well%20as%20in%20the%20LYP-1%20and%20VHR-1%20phosphatase%20selectivity%20assays.&p=BOOKS&id=280042_ml400f12.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/NBK280042/bin/ml400f12.jpg" alt="Figure 6. Dose response curves of ML400 in the LMPTP enzyme inhibition assays with OMFP and pNPP as substrates, as well as in the LYP-1 and VHR-1 phosphatase selectivity assays." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 6</span><span class="title">Dose response curves of ML400 in the LMPTP enzyme inhibition assays with OMFP and pNPP as substrates, as well as in the LYP-1 and VHR-1 phosphatase selectivity assays</span></h3></div><div id="ml400.s13"><h4>Selectivity against additional phosphatases</h4><p>The probe <a href="/pcsubstance/?term=ML400[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML400</a> and initial screening hits were found to be selective for LMPTP versus LYP-1 and VHR (usually IC50 > 80 μM for both of these). Then throughout the SAR development most of the analogs were also not active against LYP-1 and VHR, so selectivity was maintained for this preferred scaffold. Of note two analogs did have weak yet measurable activity against LYP-1 and VHR (7 -15 μM) giving us confidence that the apparent selectivity was not an artifact of the assay set up.</p></div></div><div id="ml400.s14"><h3>3.2. Cellular Activity</h3><p>The probe <a href="/pcsubstance/?term=ML400[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML400</a> was also profiled in an insulin-based mouse 3T3-L1 adipogenesis assay. We have previously found that deficiency in LMPTP expression impairs 3T3-L1 adipogenesis (Bottini laboratory unpublished observations). In this assay, 3T3-L1 pre-adipocytes are grown to 2-days post-confluence in DMEM with 10% bovine calf serum, and then induced to differentiate to adipocytes following stimulation for 2 days with an induction cocktail containing 1 μg/ml insulin, 1 μM dexamethasone, and 0.5 mM 3-isobutyl-1-methylxanthine in DMEM containing 10% fetal bovine serum (FBS).<a class="bibr" href="#ml400.r44" rid="ml400.r44">44</a> 2 days later, the media is replaced with DMEM with 10% FBS and 1 μg/ml insulin, and after 2 additional days, the media is replaced with DMEM with 10% FBS for 2 additional days, at which point adipogenesis is measured using the AdipoRed Adipogenesis Assay Reagent from Lonza, according to the manufacturer's instructions. In brief, the assay reagent is added to the wells containing cells, where it partitions into the fat droplets of differentiated adipocytes, and emits fluorescence at 572 nm that can be detected with a plate-reader. To test the effect of probe <a href="/pcsubstance/?term=ML400[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML400</a>, cells were plated into 48-well plates and allowed to grow to confluence. Cells were then treated with 10 μM <a href="/pcsubstance/?term=ML400[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML400</a> or 0.025% DMSO, and after 2 days induced to differentiate in the presence of 10 μM <a href="/pcsubstance/?term=ML400[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML400</a> or 0.025% DMSO. Fresh compound or DMSO was added during each media replacement. As shown in the <a class="figpopup" href="/books/NBK280042/figure/ml400.f13/?report=objectonly" target="object" rid-figpopup="figml400f13" rid-ob="figobml400f13">Figure 7</a>, we found that treatment with 10 μM <a href="/pcsubstance/?term=ML400[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML400</a> completely abolished 3T3-L1 adipogenesis.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml400f13" co-legend-rid="figlgndml400f13"><a href="/books/NBK280042/figure/ml400.f13/?report=objectonly" target="object" title="Figure 7" class="img_link icnblk_img figpopup" rid-figpopup="figml400f13" rid-ob="figobml400f13"><img class="small-thumb" src="/books/NBK280042/bin/ml400f13.gif" src-large="/books/NBK280042/bin/ml400f13.jpg" alt="Figure 7. ML400 Prevents Adipogenesis in 3T3-L1 Cells." /></a><div class="icnblk_cntnt" id="figlgndml400f13"><h4 id="ml400.f13"><a href="/books/NBK280042/figure/ml400.f13/?report=objectonly" target="object" rid-ob="figobml400f13">Figure 7</a></h4><p class="float-caption no_bottom_margin">ML400 Prevents Adipogenesis in 3T3-L1 Cells. </p></div></div></div><div id="ml400.s15"><h3>3.3. Profiling Assays</h3><p>From the hepatic microsome stability data the obvious candidate for <i>in vivo</i> studies is <a href="/pcsubstance/?term=ML400[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML400</a> (CID 73050863) in <a class="figpopup" href="/books/NBK280042/table/ml400.t4/?report=objectonly" target="object" rid-figpopup="figml400t4" rid-ob="figobml400t4">Table 4</a>. A Eurofin/PanLabs panel (data not shown) for <a href="/pcsubstance/?term=ML400[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML400</a> against isolated CYP isozymes show significant inhibition (77%) against only the 2D6 isoforms, while 1A2, 2C19, 2C, and 3A4 isoforms show less than 16% inhibition. Also the hepatic microsomal stability suggests that any CYP450 liabilities are manageable. <a href="/pcsubstance/?term=ML400[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML400</a> achieved very good concentrations 18-20 × IC<sub>50</sub> in aqueous buffer between a pH range of 5.0-7.4. The solubility was comparable in PBS. 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=ML400[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML400</a> showed good stability in both human plasma and mouse plasma. 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=ML400[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML400</a> showed moderate stability in human and mouse liver microsomes after 1 hour.</p><div id="ml400.s16"><h4>Mechanism of Action Studies – Mode of Inhibition characterization</h4><p>We characterized the mode of enzyme inhibition for two close analogs of <a href="/pcsubstance/?term=ML400[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML400</a> as non-competitive or uncompetitive with respect to substrates, consistent w/ potential allostery for this scaffold. Full characterization is underway in preparation for a full manuscript submission to a peer-reviewed journal.</p></div></div></div><div id="ml400.s17"><h2 id="_ml400_s17_">4. Discussion</h2><div id="ml400.s18"><h3>4.1. Comparison to existing art and how the new probe is an improvement</h3><p>Strong <i>in vitro</i>, <i>in vivo</i> and human genetic evidence suggests that LMPTP is a negative regulator of insulin signaling and a promising drug target for obesity-associated metabolic syndrome. However, other than ASOs to reduce LMPTP expression, there are currently no probes suitable for <i>in vivo</i> use to validate LMPTP as a therapeutic target. <a href="/pcsubstance/?term=ML400[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML400</a> is the <b>first selective allosteric inhibitor of LMPTP</b>. The allosteric nature confers to this probe several unique features that make it a considerable advancement to the field: 1) <a href="/pcsubstance/?term=ML400[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML400</a> was derived from a chemical series that demonstrated unparalleled selectivity for LMPTP-A against other PTPs, including not only PTP1B, but also the closely related isoform LMPTP-B; 2) the potency of <a href="/pcsubstance/?term=ML400[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML400</a> (EC<sub>50</sub>∼1 μM) is greater than that of most other LMPTP inhibitors, and within the range of the most potent reported LMPTP inhibitors (0.7-7.4 μM); 3) <a href="/pcsubstance/?term=ML400[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML400</a> displays cell-based activity at 10 μM, which is comparable to that for any other reported LMPTP inhibitors; 4) <a href="/pcsubstance/?term=ML400[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML400</a> displays promising mouse pharmacokinetics, which has never been reported for any other LMPTP inhibitors. The combined selectivity, potency and cell-permeability profile of <a href="/pcsubstance/?term=ML400[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML400</a> make this probe a “first-in-class” LMPTP inhibitor that is highly suited for preclinical experimentation in mouse models of obesity and metabolic syndrome.</p></div></div><div id="ml400.s19"><h2 id="_ml400_s19_">5. References</h2><dl class="temp-labeled-list"><dl class="bkr_refwrap"><dt>1.</dt><dd><div class="bk_ref" id="ml400.r1">Moller DE, Kaufman KD. 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Low-molecular-weight acid phosphatase (ACP1), obesity, and blood lipid levels in subjects with non-insulin-dependent diabetes mellitus. <span><span class="ref-journal">Human biology; an international record of research. </span>1997;<span class="ref-vol">69</span>:509–515.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9198310" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9198310</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>34.</dt><dd><div class="bk_ref" id="ml400.r34">Iannaccone U, Bergamaschi A, Magrini A, Marino G, Bottini N, Lucarelli P, Bottini E, Gloria-Bottini F. Serum glucose concentration and ACP1 genotype in healthy adult subjects. <span><span class="ref-journal">Metabolism: clinical and experimental. </span>2005;<span class="ref-vol">54</span>:891–894.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15988697" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15988697</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>35.</dt><dd><div class="bk_ref" id="ml400.r35">Tabernero L, Aricescu AR, Jones EY, Szedlacsek SE. Protein tyrosine phosphatases: structure function relationships. <span><span class="ref-journal">FEBS J. </span>2008;<span class="ref-vol">275</span>:867–882.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18298793" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18298793</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>36.</dt><dd><div class="bk_ref" id="ml400.r36">Maccari R, Paoli P, Ottana R, Jacomelli M, Ciurleo R, Manao G, Steindl T, Langer T, Vigorita MG, Camici G. 5-Arylidene-2,4-thiazolidinediones as inhibitors of protein tyrosine phosphatases. <span><span class="ref-journal">Bioorg Med Chem. </span>2007;<span class="ref-vol">15</span>:5137–5149.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17543532" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17543532</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>37.</dt><dd><div class="bk_ref" id="ml400.r37">Ottana R, Maccari R, Ciurleo R, Paoli P, Jacomelli M, Manao G, Camici G, Laggner C, Langer T. 5-Arylidene-2-phenylimino-4-thiazolidinones as PTP1B and LMW-PTP inhibitors. <span><span class="ref-journal">Bioorg Med Chem. </span>2009;<span class="ref-vol">17</span>:1928–1937.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/19217304" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19217304</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>38.</dt><dd><div class="bk_ref" id="ml400.r38">Maccari R, Ottana R, Ciurleo R, Paoli P, Manao G, Camici G, Laggner C, Langer T. Structure based optimization of benzoic acids as inhibitors of protein tyrosine phosphatase 1B and low molecular weight protein tyrosine phosphatase. <span><span class="ref-journal">ChemMedChem. </span>2009;<span class="ref-vol">4</span>:957–962.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/19288492" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19288492</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>39.</dt><dd><div class="bk_ref" id="ml400.r39">Forghieri M, Laggner C, Paoli P, Langer T, Manao G, Camici G, Bondioli L, Prati F, Costantino L. Synthesis, activity and molecular modeling of a new series of chromones as low molecular weight protein tyrosine phosphatase inhibitors. <span><span class="ref-journal">Bioorg Med Chem. </span>2009;<span class="ref-vol">17</span>:2658–2672.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/19297174" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19297174</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>40.</dt><dd><div class="bk_ref" id="ml400.r40">Dissing J, Rangaard B, Christensen U. Activity modulation of the fast and slow isozymes of human cytosolic low-molecular-weight acid phosphatase (ACP1) by purines. <span><span class="ref-journal">Biochimica et biophysica acta. </span>1993;<span class="ref-vol">1162</span>:275–282.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/8457591" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8457591</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>41.</dt><dd><div class="bk_ref" id="ml400.r41">Maccari, et al. Low molecular weight phosphotyrosine protein phosphatases as emerging targets for the design of novel therapeutic agents. <span><span class="ref-journal">J Med Chem. </span>2012 Jan 12;<span class="ref-vol">55</span>(1):2–22.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/21988196" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21988196</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>42.</dt><dd><div class="bk_ref" id="ml400.r42">Ottana, et al. New 4-[(5-arylidene-2-arylimino-4-oxo-3-thiazolidinyl) methyl]benzoic acids active as protein tyrosine phosphatase inhibitors endowed with insulinomimetic effect on mouse C2C12 skeletal muscle cells. <span><span class="ref-journal">Eur J Med Chem. </span>2012 Apr;<span class="ref-vol">50</span>:332–43.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/22381357" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22381357</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>43.</dt><dd><div class="bk_ref" id="ml400.r43">Seiler, et al. Identification of new inhibitors for low molecular weight protein tyrosine phosphatase isoform B. <span><span class="ref-journal">Bioorg & Med Chem Lett. </span>2013 Nov 1;<span class="ref-vol">23</span>(21):5912–4.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/24035092" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24035092</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>44.</dt><dd><div class="bk_ref" id="ml400.r44">Madsen, et al. <span><span class="ref-journal">Biochem J. </span>2003 Nov 1;<span class="ref-vol">375</span>(Pt 3):539–49.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18320708" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18320708</span></a>]</div></dd></dl></dl></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK280042_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><p class="contrib-group"><h4>Authors</h4><span itemprop="author">Robert J. Ardecky</span>,<sup>1</sup> <span itemprop="author">Michael P. Hedrick</span>,<sup>1</sup> <span itemprop="author">Stephanie M. Stanford</span>,<sup>3</sup> <span itemprop="author">Matthew R. Bliss</span>,<sup>3</sup> <span itemprop="author">Jiwen Zou</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">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">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">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> and <span itemprop="author">Nunzio Bottini</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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La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, California 92037, USA</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><h3>Publication History</h3><p class="small">Received: <span itemprop="datePublished">April 15, 2014</span>; Last Update: <span itemprop="dateModified">January 16, 2015</span>.</p><h3>Copyright</h3><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright Notice</a></div></div><h3>Publisher</h3><p>National Center for Biotechnology Information (US), Bethesda (MD)</p><h3>NLM Citation</h3><p>Ardecky RJ, Hedrick MP, Stanford SM, et al. Allosteric Small Molecule Inhibitors of LMPTP. 2014 Apr 15 [Updated 2015 Jan 16]. In: Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010-. <span class="bk_cite_avail"></span></p></div><div class="small-screen-prev"><a href="/books/n/mlprobe/ml399/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M75,30 c-80,60 -80,0 0,60 c-30,-60 -30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Prev</text></svg></a></div><div class="small-screen-next"><a href="/books/n/mlprobe/ml401/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M25,30c80,60 80,0 0,60 c30,-60 30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Next</text></svg></a></div></article><article data-type="fig" id="figobml400f1"><div id="ml400.f1" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK280042/bin/ml400f1.jpg" alt="Chemical Structure of ML400." /></div><h3><span class="title">Chemical Structure of ML400</span></h3></div></article><article data-type="table-wrap" id="figobml400t1"><div id="ml400.t1" class="table"><h3><span class="label">Table 1</span><span class="title">Potency and selectivity characteristics for probe ML400</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK280042/table/ml400.t1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml400.t1_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml400.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CID/ML#</th><th id="hd_h_ml400.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Target Name</th><th id="hd_h_ml400.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">IC<sub>50</sub> (nM)<br />[SID, AID]</th><th id="hd_h_ml400.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Anti-target Name(s)</th><th id="hd_h_ml400.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">IC<sub>50</sub> (μM)<br />[SID, AID]</th><th id="hd_h_ml400.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Fold-Selective</th><th id="hd_h_ml400.t1_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Secondary Assay(s)<br />IC<sub>50</sub> (nM)<br />[SID, AID]</th></tr></thead><tbody><tr><td headers="hd_h_ml400.t1_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:top;">CID 73050863<br /><a href="/pcsubstance/?term=ML400[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML400</a></td><td headers="hd_h_ml400.t1_1_1_1_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:top;">LMPTP<br /><br /><i>(low molecular weight protein tyrosine phosphatase)</i></td><td headers="hd_h_ml400.t1_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:top;">1680 ± 150 (n=4)<br /><br /><a href="https://pubchem.ncbi.nlm.nih.gov/substance/173019983" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 173019983</a><br /><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/686962" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 686962</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/743307" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 743307</a></td><td headers="hd_h_ml400.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">LYP-1<br /><i>(Lymphoid phosphatase, PTPN22)</i></td><td headers="hd_h_ml400.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">>80 (n=2)<br /><a href="https://pubchem.ncbi.nlm.nih.gov/substance/173019983" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 173019983</a><br /><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/743309" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 743309</a></td><td headers="hd_h_ml400.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">>60-fold</td><td headers="hd_h_ml400.t1_1_1_1_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:top;">LMPTP Orthogonal<br /><br />3520 ± 330 (n=2)<br /><br /><a href="https://pubchem.ncbi.nlm.nih.gov/substance/173019983" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 173019983</a><br /><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/743308" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 743308</a></td></tr><tr><td headers="hd_h_ml400.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><i>VHR-1</i><br /><i>(Vaccinia H1-related phosphatase)</i></td><td headers="hd_h_ml400.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">>80 (n=2)<br /><a href="https://pubchem.ncbi.nlm.nih.gov/substance/173019983" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 173019983</a><br /><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/743310" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 743310</a></td><td headers="hd_h_ml400.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">>60-fold</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobml400t2"><div id="ml400.t2" class="table"><h3><span class="label">Table 2</span><span class="title">Summary of Assays and AIDs</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK280042/table/ml400.t2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml400.t2_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml400.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">PubChemBioAssay Name</th><th id="hd_h_ml400.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">AIDs</th><th id="hd_h_ml400.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">Probe Type</th><th id="hd_h_ml400.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">Assay Type</th><th id="hd_h_ml400.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">Assay Format</th><th id="hd_h_ml400.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">Assay Detection & well format</th><th id="hd_h_ml400.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">Center</th></tr></thead><tbody><tr><td headers="hd_h_ml400.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Summary assay for small molecule inhibitors of Low Molecular Weight Protein Tyrosine Phosphatase, LMPTP</td><td headers="hd_h_ml400.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/651562" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">651562</a></td><td headers="hd_h_ml400.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Inhibitor</td><td headers="hd_h_ml400.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Summary</td><td headers="hd_h_ml400.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Biochemical</td><td headers="hd_h_ml400.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Fluorescence & 1536 well</td><td headers="hd_h_ml400.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">SBCCG</td></tr><tr><td headers="hd_h_ml400.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">uHTS identification of small molecule inhibitors of Low Molecular Weight Protein Tyrosine Phosphatase, LMPTP, via a fluorescence intensity assay</td><td headers="hd_h_ml400.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/651560" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">651560</a></td><td headers="hd_h_ml400.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Inhibitor</td><td headers="hd_h_ml400.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Primary</td><td headers="hd_h_ml400.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Biochemical</td><td headers="hd_h_ml400.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Fluorescence & 1536 well</td><td headers="hd_h_ml400.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">SBCCG</td></tr><tr><td headers="hd_h_ml400.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dose response confirmation of small molecule inhibitors of Low Molecular Weight Protein Tyrosine Phosphatase, LMPTP, via a fluorescence intensity assay</td><td headers="hd_h_ml400.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/651700" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">651700</a></td><td headers="hd_h_ml400.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Inhibitor</td><td headers="hd_h_ml400.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Confirmatory<br />(DMSO Dose Response)</td><td headers="hd_h_ml400.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Biochemical</td><td headers="hd_h_ml400.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Fluorescence & 1536 well</td><td headers="hd_h_ml400.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">SBCCG</td></tr><tr><td headers="hd_h_ml400.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dose response confirmation of small molecule inhibitors of Low Molecular Weight Protein Tyrosine Phosphatase, LMPTP, in an orthogonal absorbance-based assay</td><td headers="hd_h_ml400.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/652005" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">652005</a></td><td headers="hd_h_ml400.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Inhibitor</td><td headers="hd_h_ml400.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Orthogonal<br />(DMSO Dose Response)</td><td headers="hd_h_ml400.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Biochemical</td><td headers="hd_h_ml400.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Absorbance & 1536 well</td><td headers="hd_h_ml400.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">SBCCG</td></tr><tr><td headers="hd_h_ml400.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dose response confirmation of small molecule inhibitors of Low Molecular Weight Protein Tyrosine Phosphatase, LMPTP, in a fluorescence-based, Lymphoid Phosphatase (PTPN22, LYP-1) selectivity Assay</td><td headers="hd_h_ml400.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/652006" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">652006</a></td><td headers="hd_h_ml400.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Inhibitor</td><td headers="hd_h_ml400.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Selectivity<br />(DMSO Dose Response)</td><td headers="hd_h_ml400.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Biochemical</td><td headers="hd_h_ml400.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Fluorescence & 1536 well</td><td headers="hd_h_ml400.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">SBCCG</td></tr><tr><td headers="hd_h_ml400.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dose response confirmation of uHTS small molecule inhibitors of Low Molecular Weight Protein Tyrosine Phosphatase, LMPTP, in a fluorescence-based, VHR-1 (dual specificity phosphatase 3) selectivity assay</td><td headers="hd_h_ml400.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/686961" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">686961</a></td><td headers="hd_h_ml400.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Inhibitor</td><td headers="hd_h_ml400.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Selectivity<br />(DMSO Dose Response)</td><td headers="hd_h_ml400.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Biochemical</td><td headers="hd_h_ml400.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Fluorescence & 1536 well</td><td headers="hd_h_ml400.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">SBCCG</td></tr><tr><td headers="hd_h_ml400.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SAR confirmation of small molecule inhibitors of Low Molecular Weight Protein Tyrosine Phosphatase, LMPTP, via a fluorescence intensity assay</td><td headers="hd_h_ml400.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/686962" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">686962</a></td><td headers="hd_h_ml400.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Inhibitor</td><td headers="hd_h_ml400.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">SAR<br />(Dry Powder)</td><td headers="hd_h_ml400.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Biochemical</td><td headers="hd_h_ml400.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Fluorescence & 1536 well</td><td headers="hd_h_ml400.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">SBCCG</td></tr><tr><td headers="hd_h_ml400.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SAR confirmation of small molecule inhibitors of Low Molecular Weight Protein Tyrosine Phosphatase, LMPTP, in an orthogonal absorbance-based assay</td><td headers="hd_h_ml400.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/686963" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">686963</a></td><td headers="hd_h_ml400.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Inhibitor</td><td headers="hd_h_ml400.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">SAR<br />(Dry Powder)</td><td headers="hd_h_ml400.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Biochemical</td><td headers="hd_h_ml400.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Absorbance & 1536 well</td><td headers="hd_h_ml400.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">SBCCG</td></tr><tr><td headers="hd_h_ml400.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SAR confirmation of small molecule inhibitors of Low Molecular Weight Protein Tyrosine Phosphatase, LMPTP, via a fluorescence intensity assay, set 2</td><td headers="hd_h_ml400.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/743307" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">743307</a></td><td headers="hd_h_ml400.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Inhibitor</td><td headers="hd_h_ml400.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">SAR<br />(Dry Powder)</td><td headers="hd_h_ml400.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Biochemical</td><td headers="hd_h_ml400.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Fluorescence & 1536 well</td><td headers="hd_h_ml400.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">SBCCG</td></tr><tr><td headers="hd_h_ml400.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SAR confirmation of small molecule inhibitors of Low Molecular Weight Protein Tyrosine Phosphatase, LMPTP, in an orthogonal absorbance-based assay, set 2</td><td headers="hd_h_ml400.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/743308" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">743308</a></td><td headers="hd_h_ml400.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Inhibitor</td><td headers="hd_h_ml400.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">SAR<br />(Dry Powder)</td><td headers="hd_h_ml400.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Biochemical</td><td headers="hd_h_ml400.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Fluorescence & 1536 well</td><td headers="hd_h_ml400.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">SBCCG</td></tr><tr><td headers="hd_h_ml400.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SAR confirmation of small molecule inhibitors of Low Molecular Weight Protein Tyrosine Phosphatase, LMPTP, in a fluorescence-based, Lymphoid Phosphatase (PTPN22, LYP-1) selectivity Assay</td><td headers="hd_h_ml400.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/743309" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">743309</a></td><td headers="hd_h_ml400.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Inhibitor</td><td headers="hd_h_ml400.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">SAR<br />(Dry Powder)</td><td headers="hd_h_ml400.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Biochemical</td><td headers="hd_h_ml400.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Fluorescence & 1536 well</td><td headers="hd_h_ml400.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">SBCCG</td></tr><tr><td headers="hd_h_ml400.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SAR confirmation of uHTS small molecule inhibitors of Low Molecular Weight Protein Tyrosine Phosphatase, LMPTP, in a fluorescence-based, VHR-1 (dual specificity) selectivity assay</td><td headers="hd_h_ml400.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/743310" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">743310</a></td><td headers="hd_h_ml400.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Inhibitor</td><td headers="hd_h_ml400.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">SAR<br />(Dry Powder)</td><td headers="hd_h_ml400.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Biochemical</td><td headers="hd_h_ml400.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Fluorescence & 1536 well</td><td headers="hd_h_ml400.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">SBCCG</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobml400f2"><div id="ml400.f2" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%201.%20Structure%20of%20ML400.&p=BOOKS&id=280042_ml400f2.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK280042/bin/ml400f2.jpg" alt="Figure 1. Structure of ML400." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 1</span><span class="title">Structure of ML400</span></h3></div></article><article data-type="fig" id="figobml400f3"><div id="ml400.f3" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%202.%20Stability%20of%20ML400%20in%201%D7%20PBS%20and%201%3A1%20PBS%3AACN%20at%20RT.&p=BOOKS&id=280042_ml400f3.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK280042/bin/ml400f3.jpg" alt="Figure 2. Stability of ML400 in 1× PBS and 1:1 PBS:ACN at RT." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 2</span><span class="title">Stability of ML400 in 1× PBS and 1:1 PBS:ACN at RT</span></h3></div></article><article data-type="table-wrap" id="figobml400t3"><div id="ml400.t3" class="table"><h3><span class="label">Table 3</span><span class="title">Probe and Analog Submissions to MLSMR (Evotec) for Small Molecule Inhibitors of LMPTP</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK280042/table/ml400.t3/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml400.t3_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml400.t3_1_1_1_1" colspan="8" rowspan="1" style="text-align:center;vertical-align:middle;"><b>Probe</b>
|
|
<a href="/pcsubstance/?term=ML400[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML400</a> – <b>CID</b> 73050863</th></tr><tr><th headers="hd_h_ml400.t3_1_1_1_1" id="hd_h_ml400.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Probe/Analog</th><th headers="hd_h_ml400.t3_1_1_1_1" id="hd_h_ml400.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MLS_ID (SBCCG)</th><th headers="hd_h_ml400.t3_1_1_1_1" id="hd_h_ml400.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MLS_ID (MLSMR)</th><th headers="hd_h_ml400.t3_1_1_1_1" id="hd_h_ml400.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">CID</th><th headers="hd_h_ml400.t3_1_1_1_1" id="hd_h_ml400.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">SID</th><th headers="hd_h_ml400.t3_1_1_1_1" id="hd_h_ml400.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Source</th><th headers="hd_h_ml400.t3_1_1_1_1" id="hd_h_ml400.t3_1_1_2_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Amt (mg)</th><th headers="hd_h_ml400.t3_1_1_1_1" id="hd_h_ml400.t3_1_1_2_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Date ordered/Submitted</th></tr></thead><tbody><tr><td headers="hd_h_ml400.t3_1_1_1_1 hd_h_ml400.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Probe <a href="/pcsubstance/?term=ML400[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML400</a></td><td headers="hd_h_ml400.t3_1_1_1_1 hd_h_ml400.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0472870</td><td headers="hd_h_ml400.t3_1_1_1_1 hd_h_ml400.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MLS005939925</td><td headers="hd_h_ml400.t3_1_1_1_1 hd_h_ml400.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">73050863</td><td headers="hd_h_ml400.t3_1_1_1_1 hd_h_ml400.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/173019983" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">173019983</a></td><td headers="hd_h_ml400.t3_1_1_1_1 hd_h_ml400.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Synthesis</td><td headers="hd_h_ml400.t3_1_1_1_1 hd_h_ml400.t3_1_1_2_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">27</td><td headers="hd_h_ml400.t3_1_1_1_1 hd_h_ml400.t3_1_1_2_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">04/15/2014</td></tr><tr><td headers="hd_h_ml400.t3_1_1_1_1 hd_h_ml400.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Analog 1</td><td headers="hd_h_ml400.t3_1_1_1_1 hd_h_ml400.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0322825</td><td headers="hd_h_ml400.t3_1_1_1_1 hd_h_ml400.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MLS005939926</td><td headers="hd_h_ml400.t3_1_1_1_1 hd_h_ml400.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">2728458</td><td headers="hd_h_ml400.t3_1_1_1_1 hd_h_ml400.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/173019996" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">173019996</a></td><td headers="hd_h_ml400.t3_1_1_1_1 hd_h_ml400.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Synthesis</td><td headers="hd_h_ml400.t3_1_1_1_1 hd_h_ml400.t3_1_1_2_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">25.6</td><td headers="hd_h_ml400.t3_1_1_1_1 hd_h_ml400.t3_1_1_2_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">04/15/2014</td></tr><tr><td headers="hd_h_ml400.t3_1_1_1_1 hd_h_ml400.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Analog 2</td><td headers="hd_h_ml400.t3_1_1_1_1 hd_h_ml400.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0472782</td><td headers="hd_h_ml400.t3_1_1_1_1 hd_h_ml400.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MLS005939927</td><td headers="hd_h_ml400.t3_1_1_1_1 hd_h_ml400.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">73050855</td><td headers="hd_h_ml400.t3_1_1_1_1 hd_h_ml400.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/173019979" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">173019979</a></td><td headers="hd_h_ml400.t3_1_1_1_1 hd_h_ml400.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Synthesis</td><td headers="hd_h_ml400.t3_1_1_1_1 hd_h_ml400.t3_1_1_2_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">24.7</td><td headers="hd_h_ml400.t3_1_1_1_1 hd_h_ml400.t3_1_1_2_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">04/15/2014</td></tr><tr><td headers="hd_h_ml400.t3_1_1_1_1 hd_h_ml400.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Analog 3</td><td headers="hd_h_ml400.t3_1_1_1_1 hd_h_ml400.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0472867</td><td headers="hd_h_ml400.t3_1_1_1_1 hd_h_ml400.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MLS005939928</td><td headers="hd_h_ml400.t3_1_1_1_1 hd_h_ml400.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">73050883</td><td headers="hd_h_ml400.t3_1_1_1_1 hd_h_ml400.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/173019998" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">173019998</a></td><td headers="hd_h_ml400.t3_1_1_1_1 hd_h_ml400.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Synthesis</td><td headers="hd_h_ml400.t3_1_1_1_1 hd_h_ml400.t3_1_1_2_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">22.3</td><td headers="hd_h_ml400.t3_1_1_1_1 hd_h_ml400.t3_1_1_2_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">04/15/2014</td></tr><tr><td headers="hd_h_ml400.t3_1_1_1_1 hd_h_ml400.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Analog 4</td><td headers="hd_h_ml400.t3_1_1_1_1 hd_h_ml400.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0472866</td><td headers="hd_h_ml400.t3_1_1_1_1 hd_h_ml400.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MLS005939929</td><td headers="hd_h_ml400.t3_1_1_1_1 hd_h_ml400.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">73050881</td><td headers="hd_h_ml400.t3_1_1_1_1 hd_h_ml400.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/173019997" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">173019997</a></td><td headers="hd_h_ml400.t3_1_1_1_1 hd_h_ml400.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Synthesis</td><td headers="hd_h_ml400.t3_1_1_1_1 hd_h_ml400.t3_1_1_2_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">22.8</td><td headers="hd_h_ml400.t3_1_1_1_1 hd_h_ml400.t3_1_1_2_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">04/15/2014</td></tr><tr><td headers="hd_h_ml400.t3_1_1_1_1 hd_h_ml400.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Analog 5</td><td headers="hd_h_ml400.t3_1_1_1_1 hd_h_ml400.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0472781</td><td headers="hd_h_ml400.t3_1_1_1_1 hd_h_ml400.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MLS005939930</td><td headers="hd_h_ml400.t3_1_1_1_1 hd_h_ml400.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">73050862</td><td headers="hd_h_ml400.t3_1_1_1_1 hd_h_ml400.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/173019978" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">173019978</a></td><td headers="hd_h_ml400.t3_1_1_1_1 hd_h_ml400.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Synthesis</td><td headers="hd_h_ml400.t3_1_1_1_1 hd_h_ml400.t3_1_1_2_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">21.5</td><td headers="hd_h_ml400.t3_1_1_1_1 hd_h_ml400.t3_1_1_2_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">04/15/2014</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobml400t4"><div id="ml400.t4" class="table"><h3><span class="label">Table 4</span><span class="title">Summary of <i>in vitro</i> ADME Properties of selected LMPTP inhibitors</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK280042/table/ml400.t4/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml400.t4_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml400.t4_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Compound ID (Entry)</th><th id="hd_h_ml400.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>Aqueous Solubility</b><br /><i>Pion's buffer (ug/mL) pH 5.0/6.2/7.4</i></th><th id="hd_h_ml400.t4_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>Plasma Stability</b><br /><i>% Remaining @ 3hrs Human/Mouse</i></th><th id="hd_h_ml400.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>Hepatic Microsome Stability</b><br />% Remaining @ 1hr Human/Mouse</th></tr></thead><tbody><tr><td headers="hd_h_ml400.t4_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="/pcsubstance/?term=ML400[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML400</a></td><td headers="hd_h_ml400.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>112 / >11 / >112</td><td headers="hd_h_ml400.t4_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">89.03 / 68.97</td><td headers="hd_h_ml400.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">61.56 / 48.75</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobml400f4"><div id="ml400.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%20ML400%2C%20conditions%3A%20a.%204-Methoxybenzoyl%20chloride%2C%20DIPEA%2C%20DCM%2C%200%B0C%20to%20RT%2C%20overnight%20(80%25)%3B%20b.%20t-BuOK%2C%20t-BuOH%2C%2075%B0C%2C%20overnight%20(84%25)%3B%20c.%20POCl3%2C%2090%B0C%2C%20overnight%20(61%25)%3B%20d.%203-(Piperidin-1-yl)propan-1-amine%2C%20t-BuOK%2010%25%2C%20Dry%20DMA%2C%20135%B0C%2C%20overnight%2C%20nitrogen%20atmosphere%20(57%25).&p=BOOKS&id=280042_ml400f4.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK280042/bin/ml400f4.jpg" alt="Scheme 1. Synthesis of ML400, conditions: a. 4-Methoxybenzoyl chloride, DIPEA, DCM, 0°C to RT, overnight (80%); b. t-BuOK, t-BuOH, 75°C, overnight (84%); c. POCl3, 90°C, overnight (61%); d. 3-(Piperidin-1-yl)propan-1-amine, t-BuOK 10%, Dry DMA, 135°C, overnight, nitrogen atmosphere (57%)." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Scheme 1</span><span class="title">Synthesis of ML400, conditions: <b>a.</b> 4-Methoxybenzoyl chloride, DIPEA, DCM, 0°C to RT, overnight (80%); <b>b.</b> t-BuOK, t-BuOH, 75°C, overnight (84%); <b>c.</b> POCl3, 90°C, overnight (61%); <b>d.</b> 3-(Piperidin-1-yl)propan-1-amine, t-BuOK 10%, Dry DMA, 135°C, overnight, nitrogen atmosphere (57%)</span></h3><div class="caption"><p>(<b>Scheme 1</b>)</p></div></div></article><article data-type="fig" id="figobml400f5"><div id="ml400.f5" class="figure"><div class="graphic"><img data-src="/books/NBK280042/bin/ml400f5.jpg" alt="Image ml400f5" /></div></div></article><article data-type="fig" id="figobml400f6"><div id="ml400.f6" class="figure"><div class="graphic"><img data-src="/books/NBK280042/bin/ml400f6.jpg" alt="Image ml400f6" /></div></div></article><article data-type="fig" id="figobml400f7"><div id="ml400.f7" class="figure"><div class="graphic"><img data-src="/books/NBK280042/bin/ml400f7.jpg" alt="Image ml400f7" /></div></div></article><article data-type="fig" id="figobml400f8"><div id="ml400.f8" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK280042/bin/ml400f8.jpg" alt="ML400." /></div><h3><span class="title">ML400</span></h3></div></article><article data-type="fig" id="figobml400f9"><div id="ml400.f9" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%203.%201H%20NMR%20Spectrum%20of%20ML400%20(400%20MHz%2C%20CDCl3).&p=BOOKS&id=280042_ml400f9.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK280042/bin/ml400f9.jpg" alt="Figure 3. 1H NMR Spectrum of ML400 (400 MHz, CDCl3)." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 3</span><span class="title"><sup>1</sup>H NMR Spectrum of ML400 (400 MHz, CDCl<sub>3</sub>)</span></h3></div></article><article data-type="fig" id="figobml400f10"><div id="ml400.f10" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%204.%2013C%20NMR%20Spectrum%20of%20ML400%20(125%20MHz%2C%20CDCl3).&p=BOOKS&id=280042_ml400f10.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK280042/bin/ml400f10.jpg" alt="Figure 4. 13C NMR Spectrum of ML400 (125 MHz, CDCl3)." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 4</span><span class="title"><sup>13</sup>C NMR Spectrum of ML400 (125 MHz, CDCl<sub>3</sub>)</span></h3></div></article><article data-type="fig" id="figobml400f11"><div id="ml400.f11" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%205.%20Composite%20LC%2FMS%20for%20ML400.&p=BOOKS&id=280042_ml400f11.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK280042/bin/ml400f11.jpg" alt="Figure 5. Composite LC/MS for ML400." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 5</span><span class="title">Composite LC/MS for ML400</span></h3></div></article><article data-type="fig" id="figobml400f12"><div id="ml400.f12" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%206.%20Dose%20response%20curves%20of%20ML400%20in%20the%20LMPTP%20enzyme%20inhibition%20assays%20with%20OMFP%20and%20pNPP%20as%20substrates%2C%20as%20well%20as%20in%20the%20LYP-1%20and%20VHR-1%20phosphatase%20selectivity%20assays.&p=BOOKS&id=280042_ml400f12.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK280042/bin/ml400f12.jpg" alt="Figure 6. Dose response curves of ML400 in the LMPTP enzyme inhibition assays with OMFP and pNPP as substrates, as well as in the LYP-1 and VHR-1 phosphatase selectivity assays." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 6</span><span class="title">Dose response curves of ML400 in the LMPTP enzyme inhibition assays with OMFP and pNPP as substrates, as well as in the LYP-1 and VHR-1 phosphatase selectivity assays</span></h3></div></article><article data-type="fig" id="figobml400f13"><div id="ml400.f13" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK280042/bin/ml400f13.jpg" alt="Figure 7. ML400 Prevents Adipogenesis in 3T3-L1 Cells." /></div><h3><span class="label">Figure 7</span><span class="title">ML400 Prevents Adipogenesis in 3T3-L1 Cells</span></h3></div></article></div><div id="jr-scripts"><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/libs.min.js"> </script><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.min.js"> </script></div></div>
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