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<script type="text/javascript" src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.boots.min.js"> </script><title>Modulators of STAT Transcription Factors for the Targeted Therapy of Cancer (STAT3 Inhibitors) - 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="Modulators of STAT Transcription Factors for the Targeted Therapy of Cancer (STAT3 Inhibitors)">
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<meta name="citation_publisher" content="National Center for Biotechnology Information (US)">
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<meta name="citation_date" content="2011/03/25">
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<meta name="citation_author" content="F Madoux">
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<meta name="citation_author" content="M Koenig">
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<meta name="citation_author" content="H Sessions">
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<meta name="citation_author" content="E Nelson">
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<meta name="citation_author" content="BA Mercer">
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<meta name="citation_author" content="M Cameron">
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<meta name="citation_author" content="W Roush">
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<meta name="citation_author" content="D Frank">
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<meta name="citation_author" content="P Hodder">
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<meta name="citation_pmid" content="21735601">
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<meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK56232/">
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<meta name="DC.Title" content="Modulators of STAT Transcription Factors for the Targeted Therapy of Cancer (STAT3 Inhibitors)">
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<meta name="DC.Type" content="Text">
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<meta name="DC.Publisher" content="National Center for Biotechnology Information (US)">
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<meta name="DC.Contributor" content="F Madoux">
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<meta name="DC.Contributor" content="M Koenig">
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<meta name="DC.Contributor" content="H Sessions">
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<meta name="DC.Contributor" content="E Nelson">
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<meta name="DC.Contributor" content="BA Mercer">
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<meta name="DC.Contributor" content="M Cameron">
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<meta name="DC.Contributor" content="W Roush">
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<meta name="DC.Contributor" content="D Frank">
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<meta name="DC.Contributor" content="P Hodder">
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<meta name="DC.Date" content="2011/03/25">
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<meta name="description" content="The transcription factor STAT3 (signal transducer and activator of transcription 3) mediates the effects of growth factors and cytokines by regulating gene expression. In many human cancers, including breast and prostate, STAT3 is constitutively active. This leads to increased expression of genes regulating survival and proliferation, and drives the malignant behavior of these cells. As a result, the identification of novel compounds that selectively inhibit STAT3 activity may lead to useful tools to reduce cancer-associated cell proliferation, inflammation, and chemotherapeutic resistance. In this report we describe the identification of a potent and selective STAT3 inhibitor through the use of high throughput screening, synthetic medicinal chemistry, and molecular assays. The novel inhibitor (PubChem CID-2100018) belongs to the thienopyrimidine scaffold and is assigned probe number ML116 within the NIH Molecular Libraries Probe Production Center Network. Probe ML116 exhibits a STAT3 IC50 value of approximately 4 micromolar and does not inhibit the STAT1, STAT5, or NFkB signaling pathways (IC50 values greater than 56 micromolar), as determined using cell-based luciferase reporter assays. Quantitative PCR experiments demonstrated that probe ML116 inhibits transcription of the STAT3-regulated gene BCL3. In contrast, the gene A20 which is regulated by the unrelated transcription factor NF-kB, was not inhibited, further supporting the STAT3 selectivity of this probe. Whereas this compound can induce loss of viability of breast cancer cell lines such as MDA-MB-468 cells that are dependent on STAT3 activity, it displays essentially no toxicity to STAT3-independent SKBR3 breast cancer cells. Similar results were found in ovarian cancer cell lines and multiple myeloma cell lines. Due to the central role of aberrant STAT3 signaling in cancer pathogenesis, this compound may provide a useful starting point for the development of chemical scaffolds to block STAT3 signaling for cancer therapy.">
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<meta name="og:title" content="Modulators of STAT Transcription Factors for the Targeted Therapy of Cancer (STAT3 Inhibitors)">
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<meta name="og:description" content="The transcription factor STAT3 (signal transducer and activator of transcription 3) mediates the effects of growth factors and cytokines by regulating gene expression. In many human cancers, including breast and prostate, STAT3 is constitutively active. This leads to increased expression of genes regulating survival and proliferation, and drives the malignant behavior of these cells. As a result, the identification of novel compounds that selectively inhibit STAT3 activity may lead to useful tools to reduce cancer-associated cell proliferation, inflammation, and chemotherapeutic resistance. In this report we describe the identification of a potent and selective STAT3 inhibitor through the use of high throughput screening, synthetic medicinal chemistry, and molecular assays. The novel inhibitor (PubChem CID-2100018) belongs to the thienopyrimidine scaffold and is assigned probe number ML116 within the NIH Molecular Libraries Probe Production Center Network. Probe ML116 exhibits a STAT3 IC50 value of approximately 4 micromolar and does not inhibit the STAT1, STAT5, or NFkB signaling pathways (IC50 values greater than 56 micromolar), as determined using cell-based luciferase reporter assays. Quantitative PCR experiments demonstrated that probe ML116 inhibits transcription of the STAT3-regulated gene BCL3. In contrast, the gene A20 which is regulated by the unrelated transcription factor NF-kB, was not inhibited, further supporting the STAT3 selectivity of this probe. Whereas this compound can induce loss of viability of breast cancer cell lines such as MDA-MB-468 cells that are dependent on STAT3 activity, it displays essentially no toxicity to STAT3-independent SKBR3 breast cancer cells. Similar results were found in ovarian cancer cell lines and multiple myeloma cell lines. Due to the central role of aberrant STAT3 signaling in cancer pathogenesis, this compound may provide a useful starting point for the development of chemical scaffolds to block STAT3 signaling for cancer therapy.">
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id="jr-fip-info-p"><a id="jr-fip-prev" class="wsprkl btn" title="Jump to previuos match">◀</a><button id="jr-fip-matches">no matches yet</button><a id="jr-fip-next" class="wsprkl btn" title="Jump to next match">▶</a></nav></nav></div><div id="jr-epub-interstitial" class="hidden"></div><div id="jr-content"><article data-type="main"><div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><div class="fm-sec"><h1 id="_NBK56232_"><span class="title" itemprop="name">Modulators of STAT Transcription Factors for the Targeted Therapy of Cancer (STAT3 Inhibitors)</span></h1><p class="contribs">Madoux F, Koenig M, Sessions H, et al.</p><p class="fm-aai"><a href="#_NBK56232_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>The transcription factor STAT3 (signal transducer and activator of transcription 3) mediates the effects of growth factors and cytokines by regulating gene expression. In many human cancers, including breast and prostate, STAT3 is constitutively active. This leads to increased expression of genes regulating survival and proliferation, and drives the malignant behavior of these cells. As a result, the identification of novel compounds that selectively inhibit STAT3 activity may lead to useful tools to reduce cancer-associated cell proliferation, inflammation, and chemotherapeutic resistance. In this report we describe the identification of a potent and selective STAT3 inhibitor through the use of high throughput screening, synthetic medicinal chemistry, and molecular assays. The novel inhibitor (PubChem CID-2100018) belongs to the thienopyrimidine scaffold and is assigned probe number <a href="/pcsubstance/?term=ML116[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML116</a> within the NIH Molecular Libraries Probe Production Center Network. Probe <a href="/pcsubstance/?term=ML116[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML116</a> exhibits a STAT3 IC50 value of approximately 4 micromolar and does not inhibit the STAT1, STAT5, or NFkB signaling pathways (IC50 values greater than 56 micromolar), as determined using cell-based luciferase reporter assays. Quantitative PCR experiments demonstrated that probe <a href="/pcsubstance/?term=ML116[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML116</a> inhibits transcription of the STAT3-regulated gene BCL3. In contrast, the gene A20 which is regulated by the unrelated transcription factor NF-kB, was not inhibited, further supporting the STAT3 selectivity of this probe. Whereas this compound can induce loss of viability of breast cancer cell lines such as MDA-MB-468 cells that are dependent on STAT3 activity, it displays essentially no toxicity to STAT3-independent SKBR3 breast cancer cells. Similar results were found in ovarian cancer cell lines and multiple myeloma cell lines. Due to the central role of aberrant STAT3 signaling in cancer pathogenesis, this compound may provide a useful starting point for the development of chemical scaffolds to block STAT3 signaling for cancer therapy.</p></div><div class="h2"></div><p><b>Assigned Assay Grant #:</b> 1 X01 MH079826-01</p><p><b>Screening Center Name & PI:</b> Scripps Research Institute Molecular Screening Center (SRIMSC); Hugh Rosen</p><p><b>Chemistry Center Name & PI:</b> SRIMSC; Hugh Rosen</p><p><b>Assay Submitter & Institution:</b> David Frank, Dana Farber Cancer Institute</p><p><b>PubChem Summary Bioassay Identifier (AID):</b>
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<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1806" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1806</a></p><p><b>Probe Structure & Characteristics:</b>
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<a href="/pcsubstance/?term=ML116[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML116</a></p><div id="ml116.fu1" class="figure bk_fig"><div class="graphic"><img src="/books/NBK56232/bin/ml116fu1.jpg" alt="ML116." /></div><h3><span class="title"><a href="/pcsubstance/?term=ML116[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML116</a></span></h3></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml116tu1"><a href="/books/NBK56232/table/ml116.tu1/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figml116tu1" rid-ob="figobml116tu1"><img class="small-thumb" src="/books/NBK56232/table/ml116.tu1/?report=thumb" src-large="/books/NBK56232/table/ml116.tu1/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ml116.tu1"><a href="/books/NBK56232/table/ml116.tu1/?report=objectonly" target="object" rid-ob="figobml116tu1">Table</a></h4></div></div><p>The probe compound CID-2100018, belonging to the thienopyrimidine scaffold, is presented as a selective inhibitor of STAT3. This probe is inactive against the related STAT1 and NFκB anti-targets. In contrast, the prior art compound, nifuroxazide, is nonselective, inhibiting both STAT3 and STAT1. Additionally, qPCR experiments (run by the assay provider) confirm that the probe downregulates transcription of the oncogenes BCL3, BCL6 and BCLX, supporting the physiologic relevance of the probe. The probe does not exhibit cytotoxicity in the parental cell line used for the STAT3 assay (HT-1080).</p><div id="ml116.s1"><h2 id="_ml116_s1_">Recommendations for scientific use of the probe (<a href="/pcsubstance/?term=ML116[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML116</a>)</h2><p><i>Limitations in state of the art.</i> As prescribed in the original CPDP, the chief goal for this probe development project was to find a selective inhibitor of the signal transducer and activator of transcription 3 (STAT3). In response to this goal, the probe compound <a href="/pcsubstance/?term=ML116[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML116</a> (CID-2100018), belonging to the thienopyrimidine scaffold, is claimed as a potent and selective inhibitor of STAT3. In contrast to the prior art compounds <b>nifuroxazide</b> and <b>Stattic</b>, probe <a href="/pcsubstance/?term=ML116[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML116</a> has a low IC<sub>50</sub> for STAT3 and is inactive against the related STAT1 and NFκB anti-targets. As expected for a biologically relevant STAT3 inhibitor, QPCR experiments performed by the assay provider confirm that the probe inhibits transcription of the STAT3-regulated oncogene BCL3. In addition, the probe does not exhibit cytotoxicity in the parental cell lines used for the STAT3 assay (HT-1080), indicating that the inhibitory action was not the result off general off-target cytotoxicity or inhibition of cell growth.</p><p>Since STAT3 is downstream of several receptor and non-receptor tyrosine (Tyr) kinases, inhibitors that target the upstream acting Tyr kinase have been developed that are active against their respective targets. For example, compounds such as <b>AG490</b> and <b>WP1066</b> inhibit STAT3 activity through targeted disruption of the upstream kinase, JAK2. Unfortunately, these compounds do not target STAT3 directly, and thus induce off-target effects or their impact is not sufficiently potent to STAT3 signaling [<a class="bibr" href="#ml116.r1" rid="ml116.r1">1</a>]. Indeed, AG490 does not offer consistent antitumor effect <i>in vivo</i>, which led to the development of the more potent and blood-brain barrier penetrant WP compound [<a class="bibr" href="#ml116.r2" rid="ml116.r2">2</a>]. Additional studies are needed to validate the action of these compounds in humans.</p><p>Compounds that directly inhibit STAT3 are also reported [<a class="bibr" href="#ml116.r3" rid="ml116.r3">3</a>]. For example, <b>S3I-201</b> suppresses Stat3-dependent but not Stat3-independent transcriptional activity. Unfortunately, this compound was tested at significantly higher doses (> 30 –100 μM) than the current probe, so its activity may be the result of off-target action. Additional studies are needed.</p><p>The current probe <a href="/pcsubstance/?term=ML116[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML116</a> was identified from the STAT3 MLSCN HTS campaign. It was selected as a starting point for medicinal chemistry because of its positive results in the BCL qPCR assays. The SRIMSC probe development effort resulted in analogs that exhibited better potency against STAT3 than the probe. However, despite improved potency, these compounds showed greater inhibition in the STAT1 dose response assay, making them less attractive probe candidates due to non-selectivity. The probe is useful to study cellular STAT3 signaling, and its effect on oncogene transcription. Its minimal effect on STAT1 and NFkB activities can be exploited in cell-signaling pathway analysis. Given the qPCR results, probe <a href="/pcsubstance/?term=ML116[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML116</a> is also useful as a pharmacological tool in physiologically relevant readouts.</p><p>In summary, probe <a href="/pcsubstance/?term=ML116[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML116</a> addresses the lack of STAT3 selectivity and potency of the current state of the art.</p><p><i>Probe Applications.</i> Studies show that the signal transducer and activator of transcription 3 (STAT3) is activated in breast and prostate cancers, and that STAT3 inhibition using RNA interference or a dominant negative leads to reduced cell proliferation, survival, and wound healing (1, 3, 4, 5). Due to the diverse roles and potent phenotypes associated with STAT signaling, the identification of selective inhibitors of STAT3 activity may lead to pharmacological tools for cancer, wound healing, and inflammatory diseases.</p><p>The probe is useful to study cellular STAT3 signaling, and its effect on oncogene transcription. Its minimal effect on STAT1 and NFκB activities can be exploited in cell-signaling pathway analysis. Giving the qPCR results, it is also useful as a pharmacological tool in physiologically relevant readouts.</p><p><i>Expected end-users of the probe in the research community</i>. Probe <a href="/pcsubstance/?term=ML116[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML116</a> can be used by academic researchers studying cell biology, molecular biology, and tumor biology, breast cancer biology in particular. In addition, the identified probe will be useful for any researcher working in the field of drug discovery.</p><p><i>Relevant biology of the probe.</i> As presented in the original peer reviewed grant application, a suitable target for molecular therapies of cancer must malfunction commonly in a cancer cell, be necessary for the continued maintenance of the cancer, and be dispensable in normal cells. In recent years, much evidence has indicated that members of the STAT family of transcription factors fulfill these criteria. STAT3 is activated in a majority of breast and prostate cancers, and inhibition of this protein through the use of dominant inhibitory forms of RNA interference inhibits cell proliferation and survival [<a class="bibr" href="#ml116.r4" rid="ml116.r4">4</a>]. Studies showing that signal transducer and activator of transcription 3 (STAT3) is activated in breast and prostate cancers, that genetic inhibition of STAT3 reduces cell proliferation, survival, and wound healing [<a class="bibr" href="#ml116.r4" rid="ml116.r4 ml116.r5 ml116.r6 ml116.r7">4–7</a>]. As a result, the identification of selective STAT3 modulators may provide useful tools for exploring STAT3 biology. In particular, several lines of evidence indicate a crucial role for STAT3 proteins in selectively inducing and maintaining a pro-carcinogenic inflammatory environment, both at the initiation of malignant transformation and during cancer progression [<a class="bibr" href="#ml116.r8" rid="ml116.r8">8</a>]. Studies show that STAT3 is activated in breast and prostate cancers, and that STAT3 inhibition using RNA interference or a dominant negative leads to reduced cell proliferation, survival, and wound healing ([<a class="bibr" href="#ml116.r4" rid="ml116.r4">4</a>, <a class="bibr" href="#ml116.r6" rid="ml116.r6">6</a>, <a class="bibr" href="#ml116.r9" rid="ml116.r9">9</a>, <a class="bibr" href="#ml116.r10" rid="ml116.r10">10</a>]. In addition, reports have demonstrated that disrupting STAT3-EGFR interactions reduces tumor growth [<a class="bibr" href="#ml116.r9" rid="ml116.r9">9</a>], which suggests that STAT3 signaling has broad cellular effects. Due to the diverse roles and potent phenotypes associated with STAT signaling, the identification of selective inhibitors of STAT3 activity may lead to pharmacological tools for cancer, wound healing, and inflammatory diseases.</p></div><div id="ml116.s2"><h2 id="_ml116_s2_">1. Introduction</h2><p>The signal transducer and activator of transcription (STAT) family of transcription factors transduce signals from a variety of extracellular stimuli and are important mediators of inflammation, cell survival, differentiation, and proliferation [<a class="bibr" href="#ml116.r4" rid="ml116.r4">4</a>, <a class="bibr" href="#ml116.r7" rid="ml116.r7">7</a>]. STATs are activated in response to growth factors, cytokines, and G-CSF binding to cell surface receptor tyrosine kinases [<a class="bibr" href="#ml116.r4" rid="ml116.r4">4</a>, <a class="bibr" href="#ml116.r5" rid="ml116.r5">5</a>, <a class="bibr" href="#ml116.r7" rid="ml116.r7">7</a>]. In resting cells STATs are inactive in the cytoplasm. In response to stimuli, STATs are phosphorylated by the Janus-activated kinases (Jaks), which induces STAT dimerization and nuclear translocation, where STATs bind to specific enhancer elements in target genes [<a class="bibr" href="#ml116.r7" rid="ml116.r7">7</a>]. Although structurally similar, the seven STAT family member (STATs 1, 2, 3, 4, 5a, 5b, and 6) possess diverse biological roles [<a class="bibr" href="#ml116.r7" rid="ml116.r7">7</a>]. For example, STAT1 activation is pro-inflammatory and anti-proliferative, while STAT3 activation is anti-inflammatory and pro-apoptotic [<a class="bibr" href="#ml116.r7" rid="ml116.r7">7</a>]. STAT1 is largely responsible for mediating the effects of IFN-γ while STAT3 is predominantly involved in IL-6 signaling [<a class="bibr" href="#ml116.r6" rid="ml116.r6">6</a>]. STAT1 induces expression of genes that inhibit the cell cycle, and thus STAT1 is considered to have tumor suppressor properties [<a class="bibr" href="#ml116.r11" rid="ml116.r11">11</a>]. Studies show that STAT3 is activated in a majority of breast and prostate cancers, and that STAT3 inhibition using RNA interference or a dominant negative leads to reduced cell proliferation, survival, and wound healing [<a class="bibr" href="#ml116.r4" rid="ml116.r4">4</a>, <a class="bibr" href="#ml116.r6" rid="ml116.r6">6</a>, <a class="bibr" href="#ml116.r9" rid="ml116.r9">9</a>]. Blocking STAT3 interaction with the epidermal growth factor receptor (EGFR) using peptide aptamers has been shown to reduce tumor growth [<a class="bibr" href="#ml116.r12" rid="ml116.r12">12</a>]. Due to the diverse roles and potent phenotypes associated with STAT signaling, the identification of selective modulators of STAT3 activity may lead to pharmacological tools for cancer, wound healing, and inflammatory diseases. A common goal of the HTS screens is to identify compounds which act selectively on either STAT1 or STAT3. Compounds will be considered selective based upon their ability to modulate only one member of the STAT family. Compounds of interest should exhibit high potency and selectivity. Test compounds that do not affect STAT1::luciferase or NFkB::luciferase activities will be considered selective activators of STAT3. The novel probe identified here met these criteria.</p></div><div id="ml116.s3"><h2 id="_ml116_s3_">2. Materials and Methods</h2><p><i>Descriptions of assays follow the summary tables.</i></p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml116tu2"><a href="/books/NBK56232/table/ml116.tu2/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figml116tu2" rid-ob="figobml116tu2"><img class="small-thumb" src="/books/NBK56232/table/ml116.tu2/?report=thumb" src-large="/books/NBK56232/table/ml116.tu2/?report=previmg" alt="PubChem BioAssay Table." /></a><div class="icnblk_cntnt"><h4 id="ml116.tu2"><a href="/books/NBK56232/table/ml116.tu2/?report=objectonly" target="object" rid-ob="figobml116tu2">Table</a></h4><p class="float-caption no_bottom_margin">PubChem BioAssay Table. </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml116tu3"><a href="/books/NBK56232/table/ml116.tu3/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figml116tu3" rid-ob="figobml116tu3"><img class="small-thumb" src="/books/NBK56232/table/ml116.tu3/?report=thumb" src-large="/books/NBK56232/table/ml116.tu3/?report=previmg" alt="Table of Assay Rationale and Screening Statistics." /></a><div class="icnblk_cntnt"><h4 id="ml116.tu3"><a href="/books/NBK56232/table/ml116.tu3/?report=objectonly" target="object" rid-ob="figobml116tu3">Table</a></h4><p class="float-caption no_bottom_margin">Table of Assay Rationale and Screening Statistics. </p></div></div><div id="ml116.s4"><h3>2.1. Assays</h3><p><i>(Click on the hyperlinks to obtain itemized protocols directly from PubChem)</i></p><div id="ml116.s5"><h4>STAT3 Inhibition Assays (PubChem AIDs <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/862" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">862</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1265" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1265</a>, and <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1399" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1399</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2078" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2078</a>)</h4><p>The purpose of these assays is to determine the STAT3 percent inhibition values and dose response curves for MLSCN compounds. In these assays STAT3 inhibition was measured using a human U3A fibrosarcoma cell line that stably expresses a human STAT3::luciferase construct. This cell line is deficient in STAT1. Test compounds were screened for their ability to prevent or reduce IL-6-mediated STAT3::luciferase reporter activity. Cells were exposed to test compounds, followed by treatment with IL-6 to activate STAT3 transcription. Changes in STAT3::luciferase activity were monitored by measuring well luminescence. As designed, a STAT3 inhibitor will block IL-6-mediated STAT3 transcription, thus reducing transcription of the luciferase reporter gene, leading to decreased well luminescence. Compounds were tested at a concentration of 5.5 μM in singlicate (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/862" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-862</a>) or in triplicate (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1265" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1265</a>) and in triplicate using a 10-point, 1:3 dilution series, starting at a nominal test concentration of 55.7 μM for liquid samples (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1399" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1399</a>) and powder samples (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2078" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2078</a>).</p></div><div id="ml116.s6"><h4>STAT1 Inhibition Counterscreens (PubChem AIDs <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/920" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">920</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1317" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1317</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1411" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1411</a>, and <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2078" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2078</a>)</h4><p>The purpose of these assays is to determine the STAT1 percent inhibition values and dose response curves for MLSCN compounds. Inhibition of STAT1 activity was measured using a murine NIH 3T3 fibroblast cell line cell line that stably expresses a STAT1::luciferase construct. In the primary assay approximately 195,000 test compounds from the MLSCN library were screened for their ability to prevent or reduce IFN-gamma-mediated STAT1::luciferase reporter activity. Cells were exposed to test compounds from the MLSCN library, followed by treatment with IFN-gamma. Changes in STAT1::luciferase activity were monitored by measuring well luminescence. As designed, a STAT1 antagonist will block IFN-gamma-mediated STAT1 transcription, thus preventing or reducing the activation of the luciferase reporter gene, and decreasing luminescence. Compounds were tested at a concentration of 5.5 μM in singlicate (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/920" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-920</a>) or in triplicate (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1317" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1317</a>) and in triplicate using a 10-point, 1:3 dilution series, starting at a nominal test concentration of 55.7 μM for liquids (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1411" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1411</a>) and powder samples (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2078" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2078</a>).</p></div><div id="ml116.s7"><h4>NFkB Inhibition Counterscreen (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1308" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1308</a>)</h4><p>The purpose of this assay is to determine whether a subset of compounds identified as active in a previous set of experiments entitled, “Primary cell-based high throughput screening assay to measure STAT3 inhibition” (PubChem <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/862" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-862</a>) were nonselective STAT3 inhibitors due to inhibition of NF-kappaB. The compounds selected for testing in this AID met at least the two following criteria: 1) they were declared active in <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/862" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-862</a>; and 2) they were declared inactive in a previous set of experiments entitled, “Primary cell-based high throughput screening assay to measure STAT1 inhibition” (PubChem <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/920" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-920</a>).</p><p>In this assay inhibition of NF-kB transcription was measured using a human HEK 293T cell line that stably expresses a human NF-kB::luciferase construct. Test compounds were screened for their ability to prevent or reduce TNF-alpha-mediated induction of NF-kB::luciferase reporter activity. Cells were exposed to test compounds, followed by treatment with TNF-alpha to activate NF-kB transcription. Changes in NF-kB::luciferase activity were monitored by measuring luminescence. An inhibitor will block TNF-alpha-mediated NF-kB transcription, thus preventing or reducing the activation of the luciferase reporter gene, and decreasing well luminescence. As designed, test compounds that inhibit NF-kB activity are considered non-selective inhibitors. Compounds were tested in triplicate at a single concentration of 5.7 micromolar.</p></div><div id="ml116.s8"><h4>BCL3 QPCR Activation Counterscreens (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2078" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2078</a>)</h4><p>The purpose of this assay is to determine whether compounds of interest can inhibit the expression of the STAT3 target gene BCL3. The assay protocol has been described [<a class="bibr" href="#ml116.r10" rid="ml116.r10">10</a>]. Briefly, cells were incubated with either compound or vehicle, and RNA was isolated using the RNeasy kit (QIAGEN, Valencia, CA). cDNA was generated using the Taqman reverse transcription kit (Applied Biosystems, Foster City, CA). Quantitative real-time polymerase chain reaction (PCR) was performed in triplicate using SYBR green master mix (Applied Biosystems) on a model 7500 real time PCR system (Applied Biosystems). Data are expressed as the mean fold change plus or minus SE of 3 replicates. Compounds were tested at 10 micromolar. The reference gene was actin. The assay was repeated at least 3 times.</p></div><div id="ml116.s9"><h4>Cytotoxicity Counterscreen (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2078" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2078</a>)</h4><p>The purpose of this assay is to determine the cytotoxicity of compounds identified as STAT3 inhibitor probe candidates. This assay also serves as a counterscreen to identify false positives and non-selective compounds active in previous STAT3::luciferase inhibition assays due to cellular toxicity or inhibition of cell proliferation. This assay employs the CellTiter-Glo luminescent reagent, which contains luciferase to catalyze the oxidation of beetle luciferin to oxyluciferin and light in the presence of cellular ATP. As designed, cytotoxic compounds will reduce viable cell numbers and ATP levels, resulting in decreased well luminescence. Compounds were assayed in a 10-point 1:3 dilution series starting at a nominal concentration of 56 micromolar.</p></div></div><div id="ml116.s10"><h3>2.2. Probe Chemical Characterization</h3><p><i>Synthetic route</i>. The STAT3 inhibitor probe <a href="/pcsubstance/?term=ML116[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML116</a>was synthesized by the nucleophilic aromatic substitution sequence summarized in <a class="figpopup" href="/books/NBK56232/figure/ml116.f1/?report=objectonly" target="object" rid-figpopup="figml116f1" rid-ob="figobml116f1">Scheme 1</a>.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml116f1" co-legend-rid="figlgndml116f1"><a href="/books/NBK56232/figure/ml116.f1/?report=objectonly" target="object" title="Scheme 1" class="img_link icnblk_img figpopup" rid-figpopup="figml116f1" rid-ob="figobml116f1"><img class="small-thumb" src="/books/NBK56232/bin/ml116f1.gif" src-large="/books/NBK56232/bin/ml116f1.jpg" alt="Scheme 1. Reagents and conditions: (a) DIPEA, iPrOH, 90 °C, 2h." /></a><div class="icnblk_cntnt" id="figlgndml116f1"><h4 id="ml116.f1"><a href="/books/NBK56232/figure/ml116.f1/?report=objectonly" target="object" rid-ob="figobml116f1">Scheme 1</a></h4><p class="float-caption no_bottom_margin">Reagents and conditions: (a) DIPEA, <sup>i</sup>PrOH, 90 °C, 2h. </p></div></div><p>A number of analogs of the probe (<b>1a</b>) were synthesized according to this procedure. Data for these compounds are provided in <a class="figpopup" href="/books/NBK56232/table/ml116.t1/?report=objectonly" target="object" rid-figpopup="figml116t1" rid-ob="figobml116t1">Table 1</a> below, along with data for a selection of analogs that were obtained from a commercial source. These results show that substitution of the thiophene ring of the thienopyrimidine scaffold leads, in general, to a substantial loss of STAT3 inhibition activity (see compounds <b>1f</b> – <b>1o</b>). In contrast, substitution of the terminal aryl ring or modifications of the spacer “X” connecting the aryl ring to the piperdine ring are tolerated. In particular, replacement of X = CH<sub>2</sub> in <b>1a</b> by a ketone group (X = CO) in <b>1b</b> leads to a 5-fold increase in STAT3 inhibition in the primary assay, however this change led to a greater off-target activity for <b>1b</b> compared to <b>1a</b>. Off target activity also increased for analogs <b>1c</b>–<b>1e</b>.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml116t1"><a href="/books/NBK56232/table/ml116.t1/?report=objectonly" target="object" title="Table 1" class="img_link icnblk_img figpopup" rid-figpopup="figml116t1" rid-ob="figobml116t1"><img class="small-thumb" src="/books/NBK56232/table/ml116.t1/?report=thumb" src-large="/books/NBK56232/table/ml116.t1/?report=previmg" alt="Table 1. Substituted thienopyrimidines as STAT3 inhibitors." /></a><div class="icnblk_cntnt"><h4 id="ml116.t1"><a href="/books/NBK56232/table/ml116.t1/?report=objectonly" target="object" rid-ob="figobml116t1">Table 1</a></h4><p class="float-caption no_bottom_margin">Substituted thienopyrimidines as STAT3 inhibitors. </p></div></div><p><i>Probe chemical structure including stereochemistry. Separation of diastereomers (if necessary)</i>. The probe is achiral—there is no stereochemistry for this compound. The probe’s chemical structure is shown below.</p><div id="ml116.fu2" class="figure"><div class="graphic"><img src="/books/NBK56232/bin/ml116fu4.jpg" alt="Image ml116fu4" /></div></div><p><i>Structure verification with 1H NMR and LCMS results</i>. The title compound was obtained as a pale yellow solid (119 mg, 87%; purity: >99% by analytical HPLC). <sup>1</sup>H-NMR (400 MHz, d<sub>6</sub>-DMSO) δ 8.37 (s, 1H), 7.59 (d, <i>J</i> = 6.1 Hz, 1H), 7.54, (d, <i>J</i> = 6.2 Hz, 1H), 7.31–7.27 (m, 2H), 7.20-7.18 (m, 3H), 4.57 (d, <i>J</i> = 13.3 Hz, 2H), 3.12-3.05 (m, 2H), 2.54 (d, <i>J</i> = 7.2 Hz, 2H), 1.91-1.85 (m, 1H), 1.72-1.69 (m, 2H), 1.29-1.20 (m, 2H); <sup>13</sup>C-NMR (100 MHz, d<sub>6</sub>-DMSO) δ 168.55, 157.74, 152.56, 140.04, 129.00, 128.14, 125.80, 121.98, 121.53, 115.58, 46.69, 42.09, 37.42, 31.57; MS (m/z): 310.2 [M+1]<sup>+</sup>.</p><p><i>Solubility</i>. The solubility of the probe was measured in phosphate buffered saline (PBS: 137 mM NaCl, 2.7 mM KCl, 10 mM sodium phosphate dibasic, 2 mM potassium phosphate monobasic and a pH of 7.4) at room temperature (23°C). The solubility was found to be 1.3 μM.</p><p><i>Stability</i>. The stability of the probe was measured at room temperature (23ºC) in PBS (no antioxidants or other protectants; DMSO concentration below 0.1%). The stability, represented by the probe’s half-life, was found to be > 48 hours. Below is a graph showing the loss of compound with time over a 48 hour period with a minimum of 6 time points. The table indicates the percent of compound remaining at the end of the 48 hours.</p><div id="ml116.fu3" class="figure"><div class="graphic"><img src="/books/NBK56232/bin/ml116fu5.jpg" alt="Image ml116fu5" /></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml116tu4"><a href="/books/NBK56232/table/ml116.tu4/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figml116tu4" rid-ob="figobml116tu4"><img class="small-thumb" src="/books/NBK56232/table/ml116.tu4/?report=thumb" src-large="/books/NBK56232/table/ml116.tu4/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ml116.tu4"><a href="/books/NBK56232/table/ml116.tu4/?report=objectonly" target="object" rid-ob="figobml116tu4">Table</a></h4></div></div><p><i>The probe was measured for its ability to form glutathione adducts</i>. At concentrations of 100 μM reduced GSH, 10 μM probe does not appear to be a Michael acceptor [<a class="bibr" href="#ml116.r13" rid="ml116.r13">13</a>, <a class="bibr" href="#ml116.r14" rid="ml116.r14">14</a>].</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml116tu5"><a href="/books/NBK56232/table/ml116.tu5/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figml116tu5" rid-ob="figobml116tu5"><img class="small-thumb" src="/books/NBK56232/table/ml116.tu5/?report=thumb" src-large="/books/NBK56232/table/ml116.tu5/?report=previmg" alt="CID, SID and ML# of the probe and five related analog samples submitted to the SMR collection." /></a><div class="icnblk_cntnt"><h4 id="ml116.tu5"><a href="/books/NBK56232/table/ml116.tu5/?report=objectonly" target="object" rid-ob="figobml116tu5">Table</a></h4><p class="float-caption no_bottom_margin">CID, SID and ML# of the probe and five related analog samples submitted to the SMR collection. </p></div></div></div><div id="ml116.s11"><h3>2.3. Probe Preparation</h3><p><i>Procedure for synthesis of probe 4-(4-benzylpiperidin-1-yl)thieno[2,3-d]pyrimidine</i> (1a). A pressure vial was charged with 4-chlorothieno[2,3-d]pyrimidine (75 mg, 0.44 mmol), 4-benzylpiperidine (78 μl, 0.44 mmol), DIEA (153 μl, 0.92 mmol) and 2-propanol (2 mL). The vial was sealed and the contents were stirred at 90 ºC for 2 hours. The vessel was cooled to room temperature and saturated aqueous ammonium chloride was added. The aqueous phase was extracted with dichloromethane and the combined organic extracts dried over sodium sulfate. The solvent was removed on a rotary evaporator and the residue was purified by silica gel chromatography.</p></div></div><div id="ml116.s12"><h2 id="_ml116_s12_">3. Results</h2><div id="ml116.s13"><h3>3.1. Summary of Screening Results</h3><p>Following primary HTS in singlicate to identify STAT3 inhibitors (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/862" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-862</a>), confirmation of hit activity in triplicate (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1265" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1265</a>), counterscreening in triplicate against NFkB (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1308" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1308</a>) and STAT3 (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1317" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1317</a>) to determine selectivity, followed by titration assays to determine compound potency (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1399" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1399</a>) and selectivity (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1411" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1411</a>), compounds were identified as possible candidates for probe development. Additional STAT3 and STAT1 IC50 assays were performed, along with determinations of the effect of potential probe(s) on cell viability. Probes were identified (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2078" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2078</a>). Compared to previously described compounds, the compounds described herein offer greatly improved STAT3 selectivity and potency. The identified probe is potent, selective, and non-toxic. The novel probe compound reported here acts to inhibit STAT3 activity mediated by exposure to the known inflammatory cytokine, interleukin-6 (IL-6). This probe acts in part by reducing the transcriptional activity of the STAT3 promoter. This activity appears selective to the STAT3 signaling pathway, as no inhibition of the STAT1 pathway, NFκB pathway, or cytotoxicity was detected.</p><div id="ml116.fu4" class="figure"><div class="graphic"><img src="/books/NBK56232/bin/ml116fu6.jpg" alt="Image ml116fu6" /></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml116t2"><a href="/books/NBK56232/table/ml116.t2/?report=objectonly" target="object" title="Table 2" class="img_link icnblk_img figpopup" rid-figpopup="figml116t2" rid-ob="figobml116t2"><img class="small-thumb" src="/books/NBK56232/table/ml116.t2/?report=thumb" src-large="/books/NBK56232/table/ml116.t2/?report=previmg" alt="Table 2. uHTS campaign summary and results." /></a><div class="icnblk_cntnt"><h4 id="ml116.t2"><a href="/books/NBK56232/table/ml116.t2/?report=objectonly" target="object" rid-ob="figobml116t2">Table 2</a></h4><p class="float-caption no_bottom_margin">uHTS campaign summary and results. </p></div></div></div><div id="ml116.s14"><h3>3.2. Dose Response Curves for Probe</h3><div id="ml116.fu5" class="figure bk_fig"><div class="graphic"><img src="/books/NBK56232/bin/ml116fu7.jpg" alt="Dose-response curves of STAT3 inhibitor probe ML116 in the STAT3 and STAT1 cell-based assays." /></div><h3><span class="title">Dose-response curves of STAT3 inhibitor probe <a href="/pcsubstance/?term=ML116[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML116</a> in the STAT3 and STAT1 cell-based assays.</span></h3><div class="caption"><p> Ten-point, 1:3 serial dilution of probe compound <a href="/pcsubstance/?term=ML116[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML116</a> (<a href="https://pubchem.ncbi.nlm.nih.gov/substance/24825594" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-24825594</a>) were tested in triplicate in both the STAT3 (circles) and STAT1 (squares) inhibition assays at a starting nominal concentration of 55.7 μM using the protocols described in the technical section of this report (see AIDs <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1399" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1399</a> and <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1411" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1411</a>, respectively). Error bars represent the standard deviation of three separate experiments.</p></div></div></div><div id="ml116.s15"><h3>3.3. Scaffold/Moiety Chemical Liabilities</h3><p>Four scaffolds identified from the STAT3 inhibitor HTS campaign were deemed appropriate for initial follow-up. Structures of the lead compounds in the four scaffold series are presented below. The MLSMR was interrogated to identify analogs and structurally related compounds present in the screening deck, to begin to assemble a SAR picture. Additional analogs were identified and purchased from commercial sources testing. During this analysis, structures in the thiourea series (<a href="https://pubchem.ncbi.nlm.nih.gov/substance/22401616" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-22401616</a> and <a href="https://pubchem.ncbi.nlm.nih.gov/substance/22401426" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">22401426</a>) were de-emphasized owing to concerns about the reactivity and stability of molecules in this structural class. Therefore, the SAR by purchase efforts focused on the three series headed by compounds <a href="https://pubchem.ncbi.nlm.nih.gov/substance/24825594" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-24825594</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/substance/7971575" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">7971575</a> and<a href="https://pubchem.ncbi.nlm.nih.gov/substance/4262010" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">4262010</a>. <a href="https://pubchem.ncbi.nlm.nih.gov/substance/24825594" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-24825594</a> and <a href="https://pubchem.ncbi.nlm.nih.gov/substance/4262010" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">4262010</a> were also synthesized in order to confirm structures and activity.</p><p>The potency of the selected hits was below 2 μM in the original HTS screen. The activity of <a href="https://pubchem.ncbi.nlm.nih.gov/substance/971575" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-971575</a> could not be confirmed upon re-testing of the purchased fresh powder. The remaining three hits were found to be equally potent; however, <a href="https://pubchem.ncbi.nlm.nih.gov/substance/22401426" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-22401426</a> and <a href="https://pubchem.ncbi.nlm.nih.gov/substance/4262010" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-4262010</a> inhibited purified Luciferase activity and were consequently not considered as potential probes. Therefore, SAR efforts focused on the <a href="https://pubchem.ncbi.nlm.nih.gov/substance/24825594" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-24825594</a> scaffold series. SAR efforts concentrated on changing substituents on the thienopyrimidine core skeleton, and on the nature of the benzyl side chain. We found increased potency by inserting a ketone in the side chain (as in compounds <a href="https://pubchem.ncbi.nlm.nih.gov/substance/81080223" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-81080223</a> and <a href="https://pubchem.ncbi.nlm.nih.gov/substance/85145925" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85145925</a>). However, <a href="https://pubchem.ncbi.nlm.nih.gov/substance/24825594" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-24825594</a> was selected as the probe because unlike the more potent analogs it has a desirable biological activity profile (please see title page of this report and corresponding probe table for details). The more potent analogs also exhibited a greater level of off-target activity than for <a href="https://pubchem.ncbi.nlm.nih.gov/substance/24825594" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-24825594</a>.</p><p>Analogs were synthesized or purchased in powder form or re-ordered from the MLSMR in liquid form and tested in dose response assays against both STAT3 and STAT1. Results for these compounds are summarized in the SAR table below and in <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2078" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2078</a>.</p><div id="ml116.fu6" class="figure"><div class="graphic"><img src="/books/NBK56232/bin/ml116fu8.jpg" alt="Image ml116fu8" /></div></div><p>Ultimately, based on the efforts summarized above, a compound belonging to the <b>thienopyrimidine</b> scaffold was identified as a probe: <a href="https://pubchem.ncbi.nlm.nih.gov/substance/24825594" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-24825594</a>/CID-2100018. This compound does not share structural similarities with the known STAT3 inhibitor, nifuroxazide.</p></div><div id="ml116.s16"><h3>3.4. SAR Tables</h3><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml116t3"><a href="/books/NBK56232/table/ml116.t3/?report=objectonly" target="object" title="SAR Table 1" class="img_link icnblk_img figpopup" rid-figpopup="figml116t3" rid-ob="figobml116t3"><img class="small-thumb" src="/books/NBK56232/table/ml116.t3/?report=thumb" src-large="/books/NBK56232/table/ml116.t3/?report=previmg" alt="SAR Table 1. STAT3 Inhibitor SAR Table (Thienopyrimidine Scaffold)." /></a><div class="icnblk_cntnt"><h4 id="ml116.t3"><a href="/books/NBK56232/table/ml116.t3/?report=objectonly" target="object" rid-ob="figobml116t3">SAR Table 1</a></h4><p class="float-caption no_bottom_margin">STAT3 Inhibitor SAR Table (Thienopyrimidine Scaffold). </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml116t4"><a href="/books/NBK56232/table/ml116.t4/?report=objectonly" target="object" title="SAR Table 2" class="img_link icnblk_img figpopup" rid-figpopup="figml116t4" rid-ob="figobml116t4"><img class="small-thumb" src="/books/NBK56232/table/ml116.t4/?report=thumb" src-large="/books/NBK56232/table/ml116.t4/?report=previmg" alt="SAR Table 2. Additional synthesized and purchased analogs." /></a><div class="icnblk_cntnt"><h4 id="ml116.t4"><a href="/books/NBK56232/table/ml116.t4/?report=objectonly" target="object" rid-ob="figobml116t4">SAR Table 2</a></h4><p class="float-caption no_bottom_margin">Additional synthesized and purchased analogs. </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml116t5"><a href="/books/NBK56232/table/ml116.t5/?report=objectonly" target="object" title="SAR Table 3" class="img_link icnblk_img figpopup" rid-figpopup="figml116t5" rid-ob="figobml116t5"><img class="small-thumb" src="/books/NBK56232/table/ml116.t5/?report=thumb" src-large="/books/NBK56232/table/ml116.t5/?report=previmg" alt="SAR Table 3. Additional synthesized and purchased analogs." /></a><div class="icnblk_cntnt"><h4 id="ml116.t5"><a href="/books/NBK56232/table/ml116.t5/?report=objectonly" target="object" rid-ob="figobml116t5">SAR Table 3</a></h4><p class="float-caption no_bottom_margin">Additional synthesized and purchased analogs. </p></div></div></div><div id="ml116.s17"><h3>3.5. Cellular Activity</h3><p>The probe (<a href="/pcsubstance/?term=ML116[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML116</a>/CID-2100018/<a href="https://pubchem.ncbi.nlm.nih.gov/substance/24825594" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-24825594</a>/SR01000051757/ST3-01) was tested in a variety of cell-based assays performed by the SRIMSC and assay provider. These assays were performed to determine the probe’s selectivity for STAT3 in comparison to the related STAT1, STAT5, and NFkB signaling pathways. The results of these studies demonstrated that the probe does not inhibit STAT1, STAT5 or NFkB signaling pathways. In addition, cytotoxicity assays reveal that the selective STAT3 inhibition is not due to cytotoxicity. Whereas this probe can induce loss of viability of breast cancer cell lines dependent on STAT3 activity (such as MDA-MB-468 cells), it displays essentially no toxicity to STAT3-independent SKBR3 breast cancer cells (<b>see figure below</b>). Similar results have been found in ovarian cancer cell lines and multiple myeloma cell lines. Consequently, <a href="/pcsubstance/?term=ML116[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML116</a> is a selective and potent STAT3 inhibitor probe.</p><div id="ml116.fu7" class="figure"><div class="graphic"><img src="/books/NBK56232/bin/ml116fu30.jpg" alt="Image ml116fu30" /></div></div></div><div id="ml116.s18"><h3>3.6. Profiling Assays</h3><p>In addition to the above cellular assays, we have also obtained profiling results for the probe at 10 μM using the NCI-60 DTP Human Tumor Cell Line Screen (Background and Methods can be found at <a href="http://dtp.nci.nih.gov/branches/btb/ivclsp.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">http://dtp.nci.nih.gov/branches/btb/ivclsp.html</a>). This profiling screen examined the effect of the probe at a single high concentration (10 μM) on cellular growth of 60 well-characterized cell lines during 48 hours of exposure (significantly longer than the 6–8 hour exposure used in our cell-based reporter assays). Despite the use of this concentration which is several orders of magnitude above the EC50 of this probe, the mean cell growth among all 60 cell lines was 71% of that seen in untreated cells, as shown in the figure below. Importantly, probe <a href="/pcsubstance/?term=ML116[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML116</a> shows inhibition of growth of <u>all</u> blood cancer cell lines tested (red bars), and 4 of 5 breast cancer cell lines tested (pink bars). Thus, it is clear that this probe is a potent inhibitor of cancer cell growth at the dose range utilized in these experiments.</p><div id="ml116.fu8" class="figure"><div class="graphic"><img src="/books/NBK56232/bin/ml116fu31.jpg" alt="Image ml116fu31" /></div></div></div></div><div id="ml116.s19"><h2 id="_ml116_s19_">4. Discussion</h2><div id="ml116.s20"><h3>4.1. Comparison to existing art and how the new probe is an improvement</h3><p>As shown in the table below, the current probe <a href="/pcsubstance/?term=ML116[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML116</a> addresses the lack of STAT3 selectivity of the prior art compounds. Although several STAT3-specific agents are promising, none are in clinical development, mostly because of drug delivery and stability issues [<a class="bibr" href="#ml116.r15" rid="ml116.r15">15</a>]. In contrast, several JAK inhibitors that are orally available and ATP-competitive are in clinical development for myeloproliferative disorders.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml116tu6"><a href="/books/NBK56232/table/ml116.tu6/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figml116tu6" rid-ob="figobml116tu6"><img class="small-thumb" src="/books/NBK56232/table/ml116.tu6/?report=thumb" src-large="/books/NBK56232/table/ml116.tu6/?report=previmg" alt="Comparative Activity Table: Probe and Prior Art Compounds." /></a><div class="icnblk_cntnt"><h4 id="ml116.tu6"><a href="/books/NBK56232/table/ml116.tu6/?report=objectonly" target="object" rid-ob="figobml116tu6">Table</a></h4><p class="float-caption no_bottom_margin">Comparative Activity Table: Probe and Prior Art Compounds. </p></div></div></div><div id="ml116.s21"><h3>4.2. Mechanism of Action Studies</h3><p>In addition to the cellular and profiling assays above, it was important to determine whether the STAT3 inhibitor probe <a href="/pcsubstance/?term=ML116[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML116</a> could block expression of relevant STAT3 target genes. Thus, the assay provider performed quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) to examine the mRNA expression of a panel of STAT3 regulated genes. These assays are described [<a class="bibr" href="#ml116.r10" rid="ml116.r10">10</a>]. Briefly, cells were incubated with either compound or vehicle, and RNA was isolated using the RNeasy kit (QIAGEN, Valencia, CA). cDNA was generated using the Taqman Reverse Transcription Kit (Applied Biosystems, Foster City, CA). Quantitative real-time polymerase chain reaction (PCR) was performed in triplicate using SYBR green master mix (Applied Biosystems) on a model 7500 real time PCR system (Applied Biosystems). Data are expressed as the mean fold change plus or minus the standard error (SE) of 3 replicates, normalized to cells treated with vehicle (DMSO) alone. Each assay was repeated at least 3 times. The results (<b>see figure below</b>) show that in the STAT3-dependent OVCAR8 ovarian cancer cell line, the probe (<a href="https://pubchem.ncbi.nlm.nih.gov/substance/24825594" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-24825594</a>/CID-2100018/ST3-01) inhibits expression of four STAT3-regulated genes (Bclx, cyclin D1, Mcl1, and Smad7), consistent with its ability to block STAT3 signaling. Importantly, gene A20 which is regulated by the unrelated transcription factor, NF-kB, is not inhibited, further supporting the STAT3 selectivity of this probe. Similar results have been found in STAT3-dependent breast cancer and multiple myeloma cell lines, indicating that the STAT3 inhibitory effect is not cell type specific. It should be noted that any given gene may be regulated by multiple transcription factors, and thus patterns of changes of gene expression are more informative than responses of any individual gene.</p><div id="ml116.fu9" class="figure"><div class="graphic"><img src="/books/NBK56232/bin/ml116fu35.jpg" alt="Image ml116fu35" /></div></div><p>Given the evidence that constitutive STAT3 activation in a tumor cell drives the continued expression of genes that promote survival, it would be expected that inhibition of STAT3 would sensitize cells to undergoing apoptosis. To test this hypothesis, the effect of probe <a href="https://pubchem.ncbi.nlm.nih.gov/substance/24825594" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-24825594</a>/CID-2100018/ST3-01 was evaluated in a BH3 profiling assay that assesses the effect of an agent on the activity of modulators of mitochondrial permeability (<b>see figure above</b>). When STAT3-dependent MDA-MB-468 cells were treated with the probe for 16 hours, enhanced permeabilization of the mitochondrial outer membrane potential (MOMP) was detected with peptide mimics of PUMA or BMF, compared to vehicle treated cells. This result indicates that the probe can recapitulate the biological effects consistent with its targeted inhibition of STAT3 function.</p></div><div id="ml116.s22"><h3>4.3. Planned Future Studies</h3><p>As indicated by the assay provider, future studies with the probe will fall into three spheres: structure-activity analysis, identification of the molecular mechanism of action, and elucidation of biological effects. First, through an ongoing synthetic chemistry effort we will make structural analogues of the identified probe that will initially be tested for inhibition of STAT3-dependent gene transcription in the luciferase reporter system and subsequently with endogenous STAT3 target genes. This will provide key insights into structure-function relationships of this probe.</p><p>Second, through a series of experiments analyzing STAT3 phosphorylation, nuclear localization, DNA binding, and co-activator recruitment, we will identify the direct molecular mechanism(s) by which the probe is able to block STAT3-dependent gene expression. We will also make use of our ability to perform large scale RNA interference-based screens to identify direct molecular targets by which the probe exerts its effects.</p><p>Finally, we will examine the biological effects of the probe and analogues in both cell culture and animal models. Among the cell-based phenotypes to be explored will be cell cycle distribution, colony formation, migration, invasion, and apoptotic sensitization (both alone and in combination with clinically relevant anti-cancer therapies). The activity of the probe (and active analogues) will also be determined in STAT3-dependent tumor models in mice. This will include both xenografts of human tumors introduced into immunodeficient mice, as well as transgenic murine models that phenocopy human tumors. Where appropriate pharmacokinetic studies also will be performed to optimize dosing. For all models, tumor will be recovered so that inhibition of STAT3 function in situ can be determined as a mechanism-specific pharmacodynamic marker. The underlying hypothesis for potential medical applications is that a STAT3 inhibitor would inhibit cancer cell proliferation and survival, while causing little toxicity to normal cells. Such a molecule could represent a targeted therapy with a high therapeutic index, which may also synergize with other anti-cancer modalities.</p></div></div><div id="ml116.s23"><h2 id="_ml116_s23_">5. References</h2><dl class="temp-labeled-list"><dl class="bkr_refwrap"><dt>1.</dt><dd><div class="bk_ref" id="ml116.r1">Brantley EC, Benveniste EN. Signal transducer and activator of transcription-3: a molecular hub for signaling pathways in gliomas. <span><span class="ref-journal">Mol Cancer Res. </span>2008;<span class="ref-vol">6</span>(5):675–84.</span> [<a href="/pmc/articles/PMC3886801/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3886801</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18505913" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18505913</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>2.</dt><dd><div class="bk_ref" id="ml116.r2">Iwamaru A, Szymanski S, Iwado E, Aoki H, Yokoyama T, Fokt I, Hess K, Conrad C, Madden T, Sawaya R, Kondo S, Priebe W, Kondo Y. A novel inhibitor of the STAT3 pathway induces apoptosis in malignant glioma cells both in vitro and in vivo. <span><span class="ref-journal">Oncogene. </span>2007;<span class="ref-vol">26</span>(17):2435–44.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17043651" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17043651</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>3.</dt><dd><div class="bk_ref" id="ml116.r3">Siddiquee K, Zhang S, Guida WC, Blaskovich MA, Greedy B, Lawrence HR, Yip ML, Jove R, McLaughlin MM, Lawrence NJ, Sebti SM, Turkson J. Selective chemical probe inhibitor of Stat3, identified through structure-based virtual screening, induces antitumor activity. <span><span class="ref-journal">Proc Natl Acad Sci U S A. </span>2007;<span class="ref-vol">104</span>(18):7391–6.</span> [<a href="/pmc/articles/PMC1863497/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1863497</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/17463090" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17463090</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>4.</dt><dd><div class="bk_ref" id="ml116.r4">Alvarez JV, Febbo PG, Ramaswamy S, Loda M, Richardson A, Frank DA. Identification of a genetic signature of activated signal transducer and activator of transcription 3 in human tumors. <span><span class="ref-journal">Cancer Res. </span>2005;<span class="ref-vol">65</span>(12):5054–62.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15958548" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15958548</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>5.</dt><dd><div class="bk_ref" id="ml116.r5">Germain D, Frank DA. Targeting the cytoplasmic and nuclear functions of signal transducers and activators of transcription 3 for cancer therapy. <span><span class="ref-journal">Clin Cancer Res. </span>2007;<span class="ref-vol">13</span>(19):5665–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17908954" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17908954</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>6.</dt><dd><div class="bk_ref" id="ml116.r6">Levy DE, Darnell JE Jr. Stats: transcriptional control and biological impact. <span><span class="ref-journal">Nat Rev Mol Cell Biol. </span>2002;<span class="ref-vol">3</span>(9):651–62.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12209125" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12209125</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>7.</dt><dd><div class="bk_ref" id="ml116.r7">Schindler C, Levy DE, Decker T. JAK-STAT signaling: from interferons to cytokines. <span><span class="ref-journal">J Biol Chem. </span>2007;<span class="ref-vol">282</span>(28):20059–63.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17502367" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17502367</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>8.</dt><dd><div class="bk_ref" id="ml116.r8">Yu H, Pardoll D, Jove R. STATs in cancer inflammation and immunity: a leading role for STAT3. <span><span class="ref-journal">Nat Rev Cancer. </span>2009;<span class="ref-vol">9</span>(11):798–809.</span> [<a href="/pmc/articles/PMC4856025/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4856025</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19851315" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19851315</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>9.</dt><dd><div class="bk_ref" id="ml116.r9">Takeda K, Kaisho T, Yoshida N, Takeda J, Kishimoto T, Akira S. Stat3 activation is responsible for IL-6-dependent T cell proliferation through preventing apoptosis: generation and characterization of T cell-specific Stat3-deficient mice. <span><span class="ref-journal">J Immunol. </span>1998;<span class="ref-vol">161</span>(9):4652–60.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9794394" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9794394</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>10.</dt><dd><div class="bk_ref" id="ml116.r10">Nelson EA, Walker SR, Kepich A, Gashin LB, Hideshima T, Ikeda H, Chauhan D, Anderson KC, Frank DA. Nifuroxazide inhibits survival of multiple myeloma cells by directly inhibiting STAT3. <span><span class="ref-journal">Blood. </span>2008;<span class="ref-vol">112</span>(13):5095–102.</span> [<a href="/pmc/articles/PMC2597607/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2597607</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18824601" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18824601</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>11.</dt><dd><div class="bk_ref" id="ml116.r11">Battle TE, Wierda WG, Rassenti LZ, Zahrieh D, Neuberg D, Kipps TJ, Frank DA. In vivo activation of signal transducer and activator of transcription 1 after CD154 gene therapy for chronic lymphocytic leukemia is associated with clinical and immunologic response. <span><span class="ref-journal">Clin Cancer Res. </span>2003;<span class="ref-vol">9</span>(6):2166–72.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12796382" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12796382</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>12.</dt><dd><div class="bk_ref" id="ml116.r12">Buerger C, Nagel-Wolfrum K, Kunz C, Wittig I, Butz K, Hoppe-Seyler F, Groner B. Sequence-specific peptide aptamers, interacting with the intracellular domain of the epidermal growth factor receptor, interfere with Stat3 activation and inhibit the growth of tumor cells. <span><span class="ref-journal">J Biol Chem. </span>2003;<span class="ref-vol">278</span>(39):37610–21.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12842895" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12842895</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>13.</dt><dd><div class="bk_ref" id="ml116.r13">Li X, He Y, Ruiz CH, Koenig M, Cameron MD, Vojkovsky T. Characterization of dasatinib and its structural analogs as CYP3A4 mechanism-based inactivators and the proposed bioactivation pathways. <span><span class="ref-journal">Drug Metab Dispos. </span>2009;<span class="ref-vol">37</span>(6):1242–50.</span> [<a href="/pmc/articles/PMC3202349/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3202349</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19282395" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19282395</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>14.</dt><dd><div class="bk_ref" id="ml116.r14">Li X, Kamenecka TM, Cameron MD. Bioactivation of the epidermal growth factor receptor inhibitor gefitinib: implications for pulmonary and hepatic toxicities. <span><span class="ref-journal">Chem Res Toxicol. </span>2009;<span class="ref-vol">22</span>(10):1736–42.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/19803472" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19803472</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>15.</dt><dd><div class="bk_ref" id="ml116.r15">Lai SY, Johnson FM. Defining the role of the JAK-STAT pathway in head and neck and thoracic malignancies: implications for future therapeutic approaches. <span><span class="ref-journal">Drug Resist Updat. </span>2010;<span class="ref-vol">13</span>(3):67–78.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/20471303" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20471303</span></a>]</div></dd></dl></dl></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK56232_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><p class="contrib-group"><h4>Authors</h4><span itemprop="author">F Madoux</span>,<sup>1</sup> <span itemprop="author">M Koenig</span>,<sup>2</sup> <span itemprop="author">H Sessions</span>,<sup>2</sup> <span itemprop="author">E Nelson</span>,<sup>3</sup> <span itemprop="author">BA Mercer</span>,<sup>1</sup> <span itemprop="author">M Cameron</span>,<sup>4</sup> <span itemprop="author">W Roush</span>,<sup>2</sup> <span itemprop="author">D Frank</span>,<sup>3</sup> and <span itemprop="author">P Hodder</span><sup>1,4</sup><sup>,*</sup>.</p><h4>Affiliations</h4><div class="affiliation"><sup>1</sup>
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Lead Identification Division, Translational Research Institute, Scripps Florida, C130 Scripps Way, Jupiter, Fl, 33458</div><div class="affiliation"><sup>2</sup>
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Department of Chemistry, Scripps Florida, C130 Scripps Way, Jupiter, Fl, 33458</div><div class="affiliation"><sup>3</sup>
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Department of Medical Oncology, Dana Farber Cancer Institute, 44 Binney Street, Boston, MA 02115</div><div class="affiliation"><sup>4</sup>
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Department of Molecular Therapeutics, Scripps Florida, C130 Scripps Way, Jupiter, Fl, 33458</div><div class="affiliation">
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<sup>*</sup> To whom correspondence should be addressed,
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<span class="before-email-separator"></span><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.sppircs@preddoh" class="oemail">ude.sppircs@preddoh</a></div><h3>Publication History</h3><p class="small">Received: <span itemprop="datePublished">August 28, 2009</span>; Last Update: <span itemprop="dateModified">March 25, 2011</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>Madoux F, Koenig M, Sessions H, et al. Modulators of STAT Transcription Factors for the Targeted Therapy of Cancer (STAT3 Inhibitors) 2009 Aug 28 [Updated 2011 Mar 25]. 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/ml118/?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/ml115/?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="figobml116fu1"><div id="ml116.fu1" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK56232/bin/ml116fu1.jpg" alt="ML116." /></div><h3><span class="title"><a href="/pcsubstance/?term=ML116[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML116</a></span></h3></div></article><article data-type="table-wrap" id="figobml116tu1"><div id="ml116.tu1" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK56232/table/ml116.tu1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml116.tu1_lrgtbl__"><table><thead><tr><th id="hd_h_ml116.tu1_1_1_1_1" colspan="7" rowspan="1" style="text-align:center;vertical-align:middle;">STAT3 Inhibitor Probe: MLS 001007458<br />Thienopyrimidine Scaffold: 4-(4-benzylpiperidin-1-yl) thieno [2,3-d]pyrimidine</th></tr><tr><th headers="hd_h_ml116.tu1_1_1_1_1" id="hd_h_ml116.tu1_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID/ML</th><th headers="hd_h_ml116.tu1_1_1_1_1" id="hd_h_ml116.tu1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Target Name</th><th headers="hd_h_ml116.tu1_1_1_1_1" id="hd_h_ml116.tu1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IC50 (nM) [SID, AID]</th><th headers="hd_h_ml116.tu1_1_1_1_1" id="hd_h_ml116.tu1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Anti- target</th><th headers="hd_h_ml116.tu1_1_1_1_1" id="hd_h_ml116.tu1_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IC50 (μM) [SID, AID]</th><th headers="hd_h_ml116.tu1_1_1_1_1" id="hd_h_ml116.tu1_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Fold Selective</th><th headers="hd_h_ml116.tu1_1_1_1_1" id="hd_h_ml116.tu1_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Secondary Assays: IC50 (nM) [SID, AID]</th></tr></thead><tbody><tr><td headers="hd_h_ml116.tu1_1_1_1_1 hd_h_ml116.tu1_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID-2100018/<a href="/pcsubstance/?term=ML116[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML116</a></td><td headers="hd_h_ml116.tu1_1_1_1_1 hd_h_ml116.tu1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">STAT3</td><td headers="hd_h_ml116.tu1_1_1_1_1 hd_h_ml116.tu1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4200 nM [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/24825594" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-24825594</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2078" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2078</a>] Active</td><td headers="hd_h_ml116.tu1_1_1_1_1 hd_h_ml116.tu1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">STAT1</td><td headers="hd_h_ml116.tu1_1_1_1_1 hd_h_ml116.tu1_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 56 μM (23.52% INH) [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/24825594" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-24825594</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2078" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2078</a>] Inactive</td><td headers="hd_h_ml116.tu1_1_1_1_1 hd_h_ml116.tu1_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>13.3 fold selective</td><td headers="hd_h_ml116.tu1_1_1_1_1 hd_h_ml116.tu1_1_1_2_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><b>NFkB Counterscreen (3X%INH)</b>: 12.47%INH [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/24825594" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-24825594</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1308" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1308</a>] Inactive<br /><br /><b>HT-1080 Cytotoxicity Counterscreen</b>: [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/24825594" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-24825594</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2078" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2078</a>] Non-toxic (81.2% viability at 56 μM)<br /><br /><b>BCL3 QPCR Assay</b>: [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/24825594" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-24825594</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2078" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2078</a>] Active</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobml116tu2"><div id="ml116.tu2" class="table"><h3><span class="title">PubChem BioAssay Table</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK56232/table/ml116.tu2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml116.tu2_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml116.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">AID</th><th id="hd_h_ml116.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Assay Name</th><th id="hd_h_ml116.tu2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Assay Type</th><th id="hd_h_ml116.tu2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Target</th><th id="hd_h_ml116.tu2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Powder Sample</th><th id="hd_h_ml116.tu2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Compound Concentration</th></tr></thead><tbody><tr><td headers="hd_h_ml116.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/862" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">862</a></td><td headers="hd_h_ml116.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Primary cell-based high throughput screening assay to measure STAT3 inhibition.</td><td headers="hd_h_ml116.tu2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Primary (1X%INH)</td><td headers="hd_h_ml116.tu2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">STAT3</td><td headers="hd_h_ml116.tu2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">No</td><td headers="hd_h_ml116.tu2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5.7 μM</td></tr><tr><td headers="hd_h_ml116.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/920" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">920</a></td><td headers="hd_h_ml116.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Primary cell-based high throughput screening assay to measure STAT1 inhibition.</td><td headers="hd_h_ml116.tu2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Primary (1X%INH)</td><td headers="hd_h_ml116.tu2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">STAT1</td><td headers="hd_h_ml116.tu2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">No</td><td headers="hd_h_ml116.tu2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5.7 μM</td></tr><tr><td headers="hd_h_ml116.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1265" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1265</a></td><td headers="hd_h_ml116.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Confirmation cell-based high throughput screening assay to measure STAT3 inhibition.</td><td headers="hd_h_ml116.tu2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Confirmation (3X%INH)</td><td headers="hd_h_ml116.tu2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">STAT3</td><td headers="hd_h_ml116.tu2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">No</td><td headers="hd_h_ml116.tu2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5.7 μM</td></tr><tr><td headers="hd_h_ml116.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1308" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1308</a></td><td headers="hd_h_ml116.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Counterscreen assay for STAT3 inhibitors: Cell-based high throughput assay to measure NF-kappaB inhibition.</td><td headers="hd_h_ml116.tu2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Counterscreen (3X%INH)</td><td headers="hd_h_ml116.tu2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NFκB</td><td headers="hd_h_ml116.tu2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">No</td><td headers="hd_h_ml116.tu2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5.7 μM</td></tr><tr><td headers="hd_h_ml116.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1317" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1317</a></td><td headers="hd_h_ml116.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Counterscreen assay for STAT3 inhibitors: Cell-based high throughput assay to measure STAT1 inhibition.</td><td headers="hd_h_ml116.tu2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Counterscreen (3X %INH)</td><td headers="hd_h_ml116.tu2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">STAT1</td><td headers="hd_h_ml116.tu2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">No</td><td headers="hd_h_ml116.tu2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5.7 μM</td></tr><tr><td headers="hd_h_ml116.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1399" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1399</a></td><td headers="hd_h_ml116.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Dose response cell-based assay to measure STAT3 inhibition.</td><td headers="hd_h_ml116.tu2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Dose Response (3X IC<sub>50</sub>)</td><td headers="hd_h_ml116.tu2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">STAT3</td><td headers="hd_h_ml116.tu2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">No</td><td headers="hd_h_ml116.tu2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">10-point, 1:3 dilution starting at 55.7 μM</td></tr><tr><td headers="hd_h_ml116.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1411" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1411</a></td><td headers="hd_h_ml116.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Dose response counterscreen assay for STAT3 inhibitors: cell-based high throughput assay to measure STAT1 inhibition.</td><td headers="hd_h_ml116.tu2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Dose Response<br />Counterscreen (3X IC<sub>50</sub>)</td><td headers="hd_h_ml116.tu2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">STAT1</td><td headers="hd_h_ml116.tu2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">No</td><td headers="hd_h_ml116.tu2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">10-point, 1:3 dilution starting at 55.7 μM</td></tr><tr><td headers="hd_h_ml116.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1806" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1806</a></td><td headers="hd_h_ml116.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Summary of probe development efforts to identify inhibitors of signal transducer and activator of transcription 3 (STAT3).</td><td headers="hd_h_ml116.tu2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Summary</td><td headers="hd_h_ml116.tu2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">STAT3</td><td headers="hd_h_ml116.tu2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">No</td><td headers="hd_h_ml116.tu2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">N/A</td></tr><tr><td headers="hd_h_ml116.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2078" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2078</a></td><td headers="hd_h_ml116.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Late stage results from the probe development effort to identify inhibitors of signal transducer and activator of transcription 3 (STAT3).</td><td headers="hd_h_ml116.tu2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Late Stage</td><td headers="hd_h_ml116.tu2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">STAT3</td><td headers="hd_h_ml116.tu2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Yes</td><td headers="hd_h_ml116.tu2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Various</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobml116tu3"><div id="ml116.tu3" class="table"><h3><span class="title">Table of Assay Rationale and Screening Statistics</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK56232/table/ml116.tu3/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml116.tu3_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml116.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">AID</th><th id="hd_h_ml116.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">Assay Rationale</th><th id="hd_h_ml116.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">Assay Description</th><th id="hd_h_ml116.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">Z′</th><th id="hd_h_ml116.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">S:B</th></tr></thead><tbody><tr><td headers="hd_h_ml116.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/862" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">862</a></td><td headers="hd_h_ml116.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Identify compounds that inhibit STAT3.</td><td headers="hd_h_ml116.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">A human U3A fibrosarcoma cell line (deficient in STAT1) stably expressing a human STAT3-luciferase construct is incubated with test compounds and IL-6. Well luminescence is read after 6 hours.</td><td headers="hd_h_ml116.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.84</td><td headers="hd_h_ml116.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6.22</td></tr><tr><td headers="hd_h_ml116.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/920" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">920</a></td><td headers="hd_h_ml116.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Identify compounds that inhibit STAT1.</td><td headers="hd_h_ml116.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">A murine NIH 3T3 fibroblast cell line stably expressing STAT1-luciferase is incubated with test compounds and IFNγ. Well luminescence is read after 6 hours.</td><td headers="hd_h_ml116.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.81</td><td headers="hd_h_ml116.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">11.00</td></tr><tr><td headers="hd_h_ml116.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1265" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1265</a></td><td headers="hd_h_ml116.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Confirm activity of compounds active in <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/862" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-862</a>.</td><td headers="hd_h_ml116.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Same as <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/862" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-862</a> except that compounds are tested in triplicate.</td><td headers="hd_h_ml116.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.88</td><td headers="hd_h_ml116.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">8.04</td></tr><tr><td headers="hd_h_ml116.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1308" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1308</a></td><td headers="hd_h_ml116.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Determine whether compounds active in <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/862" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-862</a> were nonselective due to inhibition of NFκB.</td><td headers="hd_h_ml116.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">A human HEK 293T cell line stably expressing a human NFκB::luciferase construct is incubated with test compounds in the presence of TNFα. Well luminescence is read after 6 hours. Compounds are tested in triplicate.</td><td headers="hd_h_ml116.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.87</td><td headers="hd_h_ml116.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">17.60</td></tr><tr><td headers="hd_h_ml116.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1317" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1317</a></td><td headers="hd_h_ml116.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Determine whether compounds active in <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/862" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-862</a> were nonselective due to inhibition of STAT1.</td><td headers="hd_h_ml116.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Same as <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/920" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-920</a> except that compounds are tested in triplicate.</td><td headers="hd_h_ml116.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.87</td><td headers="hd_h_ml116.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">7.29</td></tr><tr><td headers="hd_h_ml116.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1399" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1399</a></td><td headers="hd_h_ml116.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Determine STAT3 inhibition dose response curves for compounds active in<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/862" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-862</a>.</td><td headers="hd_h_ml116.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Same as <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/862" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-862</a> except that compounds are tested in triplicate using a 10-point dilution series starting at 55.7 μM.</td><td headers="hd_h_ml116.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.82</td><td headers="hd_h_ml116.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6.88</td></tr><tr><td headers="hd_h_ml116.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1411" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1411</a></td><td headers="hd_h_ml116.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Determine STAT1 inhibition dose response curves for compounds active in <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/862" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-862</a>.</td><td headers="hd_h_ml116.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Same as <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/920" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-920</a> except that compounds are tested in triplicate using a 10-point dilution series starting at 55.7 μM.</td><td headers="hd_h_ml116.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.86</td><td headers="hd_h_ml116.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">14.58</td></tr><tr><td headers="hd_h_ml116.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1806" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1806</a></td><td headers="hd_h_ml116.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Summarize probe development efforts.</td><td headers="hd_h_ml116.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">N/A</td><td headers="hd_h_ml116.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">N/A</td><td headers="hd_h_ml116.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">N/A</td></tr><tr><td headers="hd_h_ml116.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2078" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2078</a></td><td headers="hd_h_ml116.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Describe the assays performed during the probe development effort.</td><td headers="hd_h_ml116.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">STAT3 Inhibition Assays, STAT1 Inhibition Counterscreen Assays, NFkB Inhibition Counterscreen Assay as above, plus additional assays to determine compound cytotoxicity.</td><td headers="hd_h_ml116.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">N/A</td><td headers="hd_h_ml116.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">N/A</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobml116f1"><div id="ml116.f1" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK56232/bin/ml116f1.jpg" alt="Scheme 1. Reagents and conditions: (a) DIPEA, iPrOH, 90 °C, 2h." /></div><h3><span class="label">Scheme 1</span><span class="title">Reagents and conditions: (a) DIPEA, <sup>i</sup>PrOH, 90 °C, 2h</span></h3></div></article><article data-type="table-wrap" id="figobml116t1"><div id="ml116.t1" class="table"><h3><span class="label">Table 1</span><span class="title">Substituted thienopyrimidines as STAT3 inhibitors</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK56232/table/ml116.t1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml116.t1_lrgtbl__"><table class="no_margin"><thead><tr><th id="hd_h_ml116.t1_1_1_1_1" colspan="6" rowspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK56232/bin/ml116fu2.jpg" alt="Image ml116fu2.jpg" /></div>
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<span class="hr"></span></th></tr><tr><th headers="hd_h_ml116.t1_1_1_1_1" id="hd_h_ml116.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">compound</th><th headers="hd_h_ml116.t1_1_1_1_1" id="hd_h_ml116.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">X</th><th headers="hd_h_ml116.t1_1_1_1_1" id="hd_h_ml116.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">R<sup>1</sup></th><th headers="hd_h_ml116.t1_1_1_1_1" id="hd_h_ml116.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">R<sup>2</sup></th><th headers="hd_h_ml116.t1_1_1_1_1" id="hd_h_ml116.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">R<sup>3</sup></th><th headers="hd_h_ml116.t1_1_1_1_1" id="hd_h_ml116.t1_1_1_2_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">STAT3 IC<sub>50</sub> (μM)</th></tr></thead><tbody><tr><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>1a</b></td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CH<sub>2</sub></td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">H</td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">H</td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">H</td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">4.2</td></tr><tr><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>1b</b></td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">C(O)</td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">H</td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">H</td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">H</td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.839</td></tr><tr><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>1c</b></td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CH<sub>2</sub></td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">F</td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">H</td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">H</td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2.53</td></tr><tr><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>1d</b></td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">C(O)</td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">F</td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">H</td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">H</td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1.69</td></tr><tr><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>1e</b></td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">C(O)</td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Cl</td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">H</td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">H</td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.837</td></tr><tr><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>1f</b><sup>*</sup></td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CH<sub>2</sub></td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">H</td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CH<sub>3</sub></td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CH<sub>3</sub></td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">>18.6</td></tr><tr><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>1g</b><sup>*</sup></td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">C(O)</td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">H</td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CH<sub>3</sub></td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CH<sub>3</sub></td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">5.21</td></tr><tr><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>1h</b><sup>*</sup></td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CHOH</td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">H</td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">H</td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">H</td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1.84</td></tr><tr><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>1i</b><sup>*</sup></td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CH<sub>2</sub></td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">H</td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_4 hd_h_ml116.t1_1_1_2_5" colspan="2" rowspan="1" style="text-align:center;vertical-align:top;">-CH<sub>2</sub>-CH<sub>2</sub>-CH<sub>2</sub>-</td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">20</td></tr><tr><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>1k</b><sup>*</sup></td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CH<sub>2</sub></td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">H</td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_4 hd_h_ml116.t1_1_1_2_5" colspan="2" rowspan="1" style="text-align:center;vertical-align:top;">-CH<sub>2</sub>-CH<sub>2</sub>-CH<sub>2</sub>-CH<sub>2</sub>-</td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">>56</td></tr><tr><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>1l</b><sup>*</sup></td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">C(O)</td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">H</td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_4 hd_h_ml116.t1_1_1_2_5" colspan="2" rowspan="1" style="text-align:center;vertical-align:top;">-CH<sub>2</sub>-CH<sub>2</sub>-CH<sub>2</sub>-CH<sub>2</sub>-</td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">>18.6</td></tr><tr><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>1m</b><sup>*</sup></td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CH<sub>2</sub></td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">H</td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK56232/bin/ml116fu3.jpg" alt="Image ml116fu3.jpg" /></div></td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">H</td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">16.7</td></tr><tr><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>1n</b><sup>*</sup></td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CH<sub>2</sub></td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">H</td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Ph</td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">H</td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">>56</td></tr><tr><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>1o</b><sup>*</sup></td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CH<sub>2</sub></td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">H</td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">H</td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Ph</td><td headers="hd_h_ml116.t1_1_1_1_1 hd_h_ml116.t1_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">>56</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>*</dt><dd><div id="ml116.tfn1"><p class="no_margin">purchased compounds</p></div></dd></dl></dl></div></div></div></article><article data-type="fig" id="figobml116fu2"><div id="ml116.fu2" class="figure"><div class="graphic"><img data-src="/books/NBK56232/bin/ml116fu4.jpg" alt="Image ml116fu4" /></div></div></article><article data-type="fig" id="figobml116fu3"><div id="ml116.fu3" class="figure"><div class="graphic"><img data-src="/books/NBK56232/bin/ml116fu5.jpg" alt="Image ml116fu5" /></div></div></article><article data-type="table-wrap" id="figobml116tu4"><div id="ml116.tu4" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK56232/table/ml116.tu4/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml116.tu4_lrgtbl__"><table><thead><tr><th id="hd_h_ml116.tu4_1_1_1_1" colspan="3" rowspan="1" style="text-align:center;vertical-align:top;">Probe <a href="/pcsubstance/?term=ML116[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML 116</a> (SR01000051757)<br />Stability in PBS Buffer (pH 7.4)</th></tr><tr><th headers="hd_h_ml116.tu4_1_1_1_1" id="hd_h_ml116.tu4_1_1_2_1" colspan="3" rowspan="1" style="text-align:left;vertical-align:top;">Sample concentration: 1 μM</th></tr><tr><th headers="hd_h_ml116.tu4_1_1_1_1 hd_h_ml116.tu4_1_1_2_1" id="hd_h_ml116.tu4_1_1_3_1" colspan="3" rowspan="1" style="text-align:left;vertical-align:top;">Storage condition: microfuge tube on lab benchtop</th></tr><tr><th headers="hd_h_ml116.tu4_1_1_1_1 hd_h_ml116.tu4_1_1_2_1 hd_h_ml116.tu4_1_1_3_1" id="hd_h_ml116.tu4_1_1_4_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Time (hr)</th><th headers="hd_h_ml116.tu4_1_1_1_1 hd_h_ml116.tu4_1_1_2_1 hd_h_ml116.tu4_1_1_3_1" id="hd_h_ml116.tu4_1_1_4_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">% remaining</th><th headers="hd_h_ml116.tu4_1_1_1_1 hd_h_ml116.tu4_1_1_2_1 hd_h_ml116.tu4_1_1_3_1" id="hd_h_ml116.tu4_1_1_4_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">In (%remaining)</th></tr></thead><tbody><tr><td headers="hd_h_ml116.tu4_1_1_1_1 hd_h_ml116.tu4_1_1_2_1 hd_h_ml116.tu4_1_1_3_1 hd_h_ml116.tu4_1_1_4_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td><td headers="hd_h_ml116.tu4_1_1_1_1 hd_h_ml116.tu4_1_1_2_1 hd_h_ml116.tu4_1_1_3_1 hd_h_ml116.tu4_1_1_4_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">100</td><td headers="hd_h_ml116.tu4_1_1_1_1 hd_h_ml116.tu4_1_1_2_1 hd_h_ml116.tu4_1_1_3_1 hd_h_ml116.tu4_1_1_4_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">4.61</td></tr><tr><td headers="hd_h_ml116.tu4_1_1_1_1 hd_h_ml116.tu4_1_1_2_1 hd_h_ml116.tu4_1_1_3_1 hd_h_ml116.tu4_1_1_4_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1</td><td headers="hd_h_ml116.tu4_1_1_1_1 hd_h_ml116.tu4_1_1_2_1 hd_h_ml116.tu4_1_1_3_1 hd_h_ml116.tu4_1_1_4_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">87</td><td headers="hd_h_ml116.tu4_1_1_1_1 hd_h_ml116.tu4_1_1_2_1 hd_h_ml116.tu4_1_1_3_1 hd_h_ml116.tu4_1_1_4_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">4.47</td></tr><tr><td headers="hd_h_ml116.tu4_1_1_1_1 hd_h_ml116.tu4_1_1_2_1 hd_h_ml116.tu4_1_1_3_1 hd_h_ml116.tu4_1_1_4_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml116.tu4_1_1_1_1 hd_h_ml116.tu4_1_1_2_1 hd_h_ml116.tu4_1_1_3_1 hd_h_ml116.tu4_1_1_4_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">103</td><td headers="hd_h_ml116.tu4_1_1_1_1 hd_h_ml116.tu4_1_1_2_1 hd_h_ml116.tu4_1_1_3_1 hd_h_ml116.tu4_1_1_4_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">4.63</td></tr><tr><td headers="hd_h_ml116.tu4_1_1_1_1 hd_h_ml116.tu4_1_1_2_1 hd_h_ml116.tu4_1_1_3_1 hd_h_ml116.tu4_1_1_4_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">4</td><td headers="hd_h_ml116.tu4_1_1_1_1 hd_h_ml116.tu4_1_1_2_1 hd_h_ml116.tu4_1_1_3_1 hd_h_ml116.tu4_1_1_4_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">104</td><td headers="hd_h_ml116.tu4_1_1_1_1 hd_h_ml116.tu4_1_1_2_1 hd_h_ml116.tu4_1_1_3_1 hd_h_ml116.tu4_1_1_4_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">4.64</td></tr><tr><td headers="hd_h_ml116.tu4_1_1_1_1 hd_h_ml116.tu4_1_1_2_1 hd_h_ml116.tu4_1_1_3_1 hd_h_ml116.tu4_1_1_4_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">8</td><td headers="hd_h_ml116.tu4_1_1_1_1 hd_h_ml116.tu4_1_1_2_1 hd_h_ml116.tu4_1_1_3_1 hd_h_ml116.tu4_1_1_4_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">105</td><td headers="hd_h_ml116.tu4_1_1_1_1 hd_h_ml116.tu4_1_1_2_1 hd_h_ml116.tu4_1_1_3_1 hd_h_ml116.tu4_1_1_4_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">4.65</td></tr><tr><td headers="hd_h_ml116.tu4_1_1_1_1 hd_h_ml116.tu4_1_1_2_1 hd_h_ml116.tu4_1_1_3_1 hd_h_ml116.tu4_1_1_4_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">24</td><td headers="hd_h_ml116.tu4_1_1_1_1 hd_h_ml116.tu4_1_1_2_1 hd_h_ml116.tu4_1_1_3_1 hd_h_ml116.tu4_1_1_4_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">124</td><td headers="hd_h_ml116.tu4_1_1_1_1 hd_h_ml116.tu4_1_1_2_1 hd_h_ml116.tu4_1_1_3_1 hd_h_ml116.tu4_1_1_4_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">4.82</td></tr><tr><td headers="hd_h_ml116.tu4_1_1_1_1 hd_h_ml116.tu4_1_1_2_1 hd_h_ml116.tu4_1_1_3_1 hd_h_ml116.tu4_1_1_4_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">48</td><td headers="hd_h_ml116.tu4_1_1_1_1 hd_h_ml116.tu4_1_1_2_1 hd_h_ml116.tu4_1_1_3_1 hd_h_ml116.tu4_1_1_4_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">121</td><td headers="hd_h_ml116.tu4_1_1_1_1 hd_h_ml116.tu4_1_1_2_1 hd_h_ml116.tu4_1_1_3_1 hd_h_ml116.tu4_1_1_4_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">4.80</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobml116tu5"><div id="ml116.tu5" class="table"><h3><span class="title">CID, SID and ML# of the probe and five related analog samples submitted to the SMR collection</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK56232/table/ml116.tu5/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml116.tu5_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml116.tu5_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">Compound</th><th id="hd_h_ml116.tu5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">SR Number</th><th id="hd_h_ml116.tu5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">MLS</th><th id="hd_h_ml116.tu5_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">CID</th><th id="hd_h_ml116.tu5_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">SID</th></tr></thead><tbody><tr><td headers="hd_h_ml116.tu5_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Probe <a href="/pcsubstance/?term=ML116[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML116</a></td><td headers="hd_h_ml116.tu5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">SR-01000051757</td><td headers="hd_h_ml116.tu5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">MLS001007458</td><td headers="hd_h_ml116.tu5_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2100018</td><td headers="hd_h_ml116.tu5_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/24825594" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">24825594</a> (liquid); <a href="https://pubchem.ncbi.nlm.nih.gov/substance/87326012" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">87326012</a> (powder)</td></tr><tr><td headers="hd_h_ml116.tu5_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Analog 1</td><td headers="hd_h_ml116.tu5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">SR-03000000949</td><td headers="hd_h_ml116.tu5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">MLS002473459</td><td headers="hd_h_ml116.tu5_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">41724711</td><td headers="hd_h_ml116.tu5_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/81080223" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">81080223</a></td></tr><tr><td headers="hd_h_ml116.tu5_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Analog 2</td><td headers="hd_h_ml116.tu5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">SR-03000000948</td><td headers="hd_h_ml116.tu5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">MLS002473458</td><td headers="hd_h_ml116.tu5_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">42640809</td><td headers="hd_h_ml116.tu5_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/81080222" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">81080222</a></td></tr><tr><td headers="hd_h_ml116.tu5_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Analog 3</td><td headers="hd_h_ml116.tu5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">SR-03000000947</td><td headers="hd_h_ml116.tu5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">MLS002473457</td><td headers="hd_h_ml116.tu5_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">42640808</td><td headers="hd_h_ml116.tu5_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/81080221" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">81080221</a></td></tr><tr><td headers="hd_h_ml116.tu5_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Analog 4</td><td headers="hd_h_ml116.tu5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">SR-03000001009</td><td headers="hd_h_ml116.tu5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">MLS002473641</td><td headers="hd_h_ml116.tu5_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">44141938</td><td headers="hd_h_ml116.tu5_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85145925" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85145925</a></td></tr><tr><td headers="hd_h_ml116.tu5_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Analog 5</td><td headers="hd_h_ml116.tu5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">SR-01000309219</td><td headers="hd_h_ml116.tu5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">MLS000736205</td><td headers="hd_h_ml116.tu5_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1478199</td><td headers="hd_h_ml116.tu5_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/24824606" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">24824606</a></td></tr></tbody></table></div></div></article><article data-type="fig" id="figobml116fu4"><div id="ml116.fu4" class="figure"><div class="graphic"><img data-src="/books/NBK56232/bin/ml116fu6.jpg" alt="Image ml116fu6" /></div></div></article><article data-type="table-wrap" id="figobml116t2"><div id="ml116.t2" class="table"><h3><span class="label">Table 2</span><span class="title">uHTS campaign summary and results</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK56232/table/ml116.t2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml116.t2_lrgtbl__"><table class="no_margin"><thead><tr><th id="hd_h_ml116.t2_1_1_1_1" rowspan="2" colspan="1" headers="hd_h_ml116.t2_1_1_1_1" style="text-align:center;vertical-align:middle;">Step</th><th id="hd_h_ml116.t2_1_1_1_2" rowspan="2" colspan="1" headers="hd_h_ml116.t2_1_1_1_2" style="text-align:center;vertical-align:middle;">Screen type</th><th id="hd_h_ml116.t2_1_1_1_3" rowspan="2" colspan="1" headers="hd_h_ml116.t2_1_1_1_3" style="text-align:center;vertical-align:middle;">Target</th><th id="hd_h_ml116.t2_1_1_1_4" rowspan="2" colspan="1" headers="hd_h_ml116.t2_1_1_1_4" style="text-align:center;vertical-align:middle;">Number of compounds tested</th><th id="hd_h_ml116.t2_1_1_1_5" rowspan="2" colspan="1" headers="hd_h_ml116.t2_1_1_1_5" style="text-align:center;vertical-align:middle;">Selection criteria</th><th id="hd_h_ml116.t2_1_1_1_6" rowspan="2" colspan="1" headers="hd_h_ml116.t2_1_1_1_6" style="text-align:center;vertical-align:middle;">Number of selected compounds</th><th id="hd_h_ml116.t2_1_1_1_7" rowspan="2" colspan="1" headers="hd_h_ml116.t2_1_1_1_7" style="text-align:center;vertical-align:middle;">PubChem AID<sup>c</sup></th><th id="hd_h_ml116.t2_1_1_1_8" colspan="2" rowspan="1" style="text-align:center;vertical-align:middle;">Assay statistics
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<span class="hr"></span></th></tr><tr><th headers="hd_h_ml116.t2_1_1_1_8" id="hd_h_ml116.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Z′</th><th headers="hd_h_ml116.t2_1_1_1_8" id="hd_h_ml116.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S/B</th></tr></thead><tbody><tr><td headers="hd_h_ml116.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1</td><td headers="hd_h_ml116.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Primary screen</td><td headers="hd_h_ml116.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">STAT3</td><td headers="hd_h_ml116.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">194698</td><td headers="hd_h_ml116.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">%Inh<sup>a</sup>>43.4%</td><td headers="hd_h_ml116.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1723</td><td headers="hd_h_ml116.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/862" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">862</a></td><td headers="hd_h_ml116.t2_1_1_1_8 hd_h_ml116.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.84</td><td headers="hd_h_ml116.t2_1_1_1_8 hd_h_ml116.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">6.22</td></tr><tr><td headers="hd_h_ml116.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml116.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Confirmation</td><td headers="hd_h_ml116.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">STAT3</td><td headers="hd_h_ml116.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1215</td><td headers="hd_h_ml116.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">%Inh<sup>b</sup>>43.4%</td><td headers="hd_h_ml116.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">544</td><td headers="hd_h_ml116.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1265" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1265</a></td><td headers="hd_h_ml116.t2_1_1_1_8 hd_h_ml116.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.88</td><td headers="hd_h_ml116.t2_1_1_1_8 hd_h_ml116.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">8.04</td></tr><tr><td headers="hd_h_ml116.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3a</td><td headers="hd_h_ml116.t2_1_1_1_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">Selectivity</td><td headers="hd_h_ml116.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NF-kB</td><td headers="hd_h_ml116.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">544</td><td headers="hd_h_ml116.t2_1_1_1_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">Inactive in both the NF-κB and STAT1 assays</td><td headers="hd_h_ml116.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">105</td><td headers="hd_h_ml116.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1308" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1308</a></td><td headers="hd_h_ml116.t2_1_1_1_8 hd_h_ml116.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.87</td><td headers="hd_h_ml116.t2_1_1_1_8 hd_h_ml116.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">17.60</td></tr><tr><td headers="hd_h_ml116.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3b</td><td headers="hd_h_ml116.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">STAT1</td><td headers="hd_h_ml116.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">105</td><td headers="hd_h_ml116.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">87</td><td headers="hd_h_ml116.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1317" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1317</a></td><td headers="hd_h_ml116.t2_1_1_1_8 hd_h_ml116.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.87</td><td headers="hd_h_ml116.t2_1_1_1_8 hd_h_ml116.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">7.29</td></tr><tr><td headers="hd_h_ml116.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">4a</td><td headers="hd_h_ml116.t2_1_1_1_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">Titration</td><td headers="hd_h_ml116.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">STAT3</td><td headers="hd_h_ml116.t2_1_1_1_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">122</td><td headers="hd_h_ml116.t2_1_1_1_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">Active in the STAT3 assay and inactive in the STAT1 assay</td><td headers="hd_h_ml116.t2_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">116</td><td headers="hd_h_ml116.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1399" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1399</a></td><td headers="hd_h_ml116.t2_1_1_1_8 hd_h_ml116.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.82</td><td headers="hd_h_ml116.t2_1_1_1_8 hd_h_ml116.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">6.88</td></tr><tr><td headers="hd_h_ml116.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">4b</td><td headers="hd_h_ml116.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">STAT1</td><td headers="hd_h_ml116.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1411" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1411</a></td><td headers="hd_h_ml116.t2_1_1_1_8 hd_h_ml116.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.86</td><td headers="hd_h_ml116.t2_1_1_1_8 hd_h_ml116.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">14.58</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>a</dt><dd><div id="ml116.tfn2"><p class="no_margin">The primary screen hit-cutoff was calculated at the average percent activation of all test compounds plus three times the standard deviation.</p></div></dd></dl><dl class="bkr_refwrap"><dt>b</dt><dd><div id="ml116.tfn3"><p class="no_margin">The hit-cutoff calculated for the primary run was also applied to the confirmation run.</p></div></dd></dl><dl class="bkr_refwrap"><dt>c</dt><dd><div id="ml116.tfn4"><p class="no_margin">PubChem AIDs are accessible on-line at <a href="/sites/entrez?db=pcassay&term=xxxx" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">http://www<wbr style="display:inline-block"></wbr>​.ncbi.nlm.nih<wbr style="display:inline-block"></wbr>​.gov/sites/entrez?db<wbr style="display:inline-block"></wbr>​=pcassay&term=xxxx</a>, where xxxx represents the PubChem AID number listed in the table.</p></div></dd></dl></dl></div></div></div></article><article data-type="fig" id="figobml116fu5"><div id="ml116.fu5" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK56232/bin/ml116fu7.jpg" alt="Dose-response curves of STAT3 inhibitor probe ML116 in the STAT3 and STAT1 cell-based assays." /></div><h3><span class="title">Dose-response curves of STAT3 inhibitor probe <a href="/pcsubstance/?term=ML116[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML116</a> in the STAT3 and STAT1 cell-based assays.</span></h3><div class="caption"><p> Ten-point, 1:3 serial dilution of probe compound <a href="/pcsubstance/?term=ML116[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML116</a> (<a href="https://pubchem.ncbi.nlm.nih.gov/substance/24825594" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-24825594</a>) were tested in triplicate in both the STAT3 (circles) and STAT1 (squares) inhibition assays at a starting nominal concentration of 55.7 μM using the protocols described in the technical section of this report (see AIDs <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1399" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1399</a> and <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1411" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1411</a>, respectively). Error bars represent the standard deviation of three separate experiments.</p></div></div></article><article data-type="fig" id="figobml116fu6"><div id="ml116.fu6" class="figure"><div class="graphic"><img data-src="/books/NBK56232/bin/ml116fu8.jpg" alt="Image ml116fu8" /></div></div></article><article data-type="table-wrap" id="figobml116t3"><div id="ml116.t3" class="table"><h3><span class="label">SAR Table 1</span><span class="title">STAT3 Inhibitor SAR Table (Thienopyrimidine Scaffold)</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK56232/table/ml116.t3/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml116.t3_lrgtbl__"><table class="no_margin"><thead><tr><th id="hd_h_ml116.t3_1_1_1_1" colspan="8" rowspan="1" style="text-align:center;vertical-align:middle;">Compound Information</th><th id="hd_h_ml116.t3_1_1_1_2" colspan="7" rowspan="1" style="text-align:center;vertical-align:middle;">Screening Assays</th><th id="hd_h_ml116.t3_1_1_1_3" colspan="4" rowspan="1" style="text-align:center;vertical-align:middle;">Probe Development (AIDs <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1806" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1806</a> and <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2078" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2078</a>)</th></tr><tr><th headers="hd_h_ml116.t3_1_1_1_1" id="hd_h_ml116.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Compound</th><th headers="hd_h_ml116.t3_1_1_1_1" id="hd_h_ml116.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Scripps ID</th><th headers="hd_h_ml116.t3_1_1_1_1" id="hd_h_ml116.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Structure</th><th headers="hd_h_ml116.t3_1_1_1_1" id="hd_h_ml116.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID</th><th headers="hd_h_ml116.t3_1_1_1_1" id="hd_h_ml116.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SID</th><th headers="hd_h_ml116.t3_1_1_1_1" id="hd_h_ml116.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS ID</th><th headers="hd_h_ml116.t3_1_1_1_1" id="hd_h_ml116.t3_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Vendor</th><th headers="hd_h_ml116.t3_1_1_1_1" id="hd_h_ml116.t3_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Vendor Catalog ID</th><th headers="hd_h_ml116.t3_1_1_1_2" id="hd_h_ml116.t3_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">STAT3 Primary (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/862" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-862</a>: %INH)</th><th headers="hd_h_ml116.t3_1_1_1_2" id="hd_h_ml116.t3_1_1_2_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">STAT1 Primary (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/920" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-920</a>: %INH)</th><th headers="hd_h_ml116.t3_1_1_1_2" id="hd_h_ml116.t3_1_1_2_11" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">STAT3 Confirmation (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1265" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1265</a>: %INH)</th><th headers="hd_h_ml116.t3_1_1_1_2" id="hd_h_ml116.t3_1_1_2_12" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NFkB (3X Counterscreen (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1308" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1308</a>: %INH)</th><th headers="hd_h_ml116.t3_1_1_1_2" id="hd_h_ml116.t3_1_1_2_13" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">STAT1 (3X Counterscreen (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1317" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1317</a>: %INH)</th><th headers="hd_h_ml116.t3_1_1_1_2" id="hd_h_ml116.t3_1_1_2_14" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">STAT3 Dose Response (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1399" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1399</a>: IC50, μM)</th><th headers="hd_h_ml116.t3_1_1_1_2" id="hd_h_ml116.t3_1_1_2_15" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">STAT1 Dose Response Counterscreen (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1411" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1411</a>: IC50, μM)</th><th headers="hd_h_ml116.t3_1_1_1_3" id="hd_h_ml116.t3_1_1_2_16" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">STAT3 IC50 (μM)</th><th headers="hd_h_ml116.t3_1_1_1_3" id="hd_h_ml116.t3_1_1_2_17" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">STAT1 IC50 (μM)</th><th headers="hd_h_ml116.t3_1_1_1_3" id="hd_h_ml116.t3_1_1_2_18" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Cytotoxicity Assay</th><th headers="hd_h_ml116.t3_1_1_1_3" id="hd_h_ml116.t3_1_1_2_19" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">qPCR Assay</th></tr></thead><tbody><tr><td headers="hd_h_ml116.t3_1_1_1_1 hd_h_ml116.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>STAT3 Inhibitor PROBE</b></td><td headers="hd_h_ml116.t3_1_1_1_1 hd_h_ml116.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SR- 01000051757</td><td headers="hd_h_ml116.t3_1_1_1_1 hd_h_ml116.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK56232/bin/ml116fu9.jpg" alt="Image ml116fu9.jpg" /></div></td><td headers="hd_h_ml116.t3_1_1_1_1 hd_h_ml116.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2100018</td><td headers="hd_h_ml116.t3_1_1_1_1 hd_h_ml116.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/24825594" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">24825594</a></td><td headers="hd_h_ml116.t3_1_1_1_1 hd_h_ml116.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS 001007458</td><td headers="hd_h_ml116.t3_1_1_1_1 hd_h_ml116.t3_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Enamine</td><td headers="hd_h_ml116.t3_1_1_1_1 hd_h_ml116.t3_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">T5234097</td><td headers="hd_h_ml116.t3_1_1_1_2 hd_h_ml116.t3_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Active (83.2)</td><td headers="hd_h_ml116.t3_1_1_1_2 hd_h_ml116.t3_1_1_2_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Inactive (25.97)</td><td headers="hd_h_ml116.t3_1_1_1_2 hd_h_ml116.t3_1_1_2_11" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Active (78.9)</td><td headers="hd_h_ml116.t3_1_1_1_2 hd_h_ml116.t3_1_1_2_12" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Inactive (12.47)</td><td headers="hd_h_ml116.t3_1_1_1_2 hd_h_ml116.t3_1_1_2_13" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Inactive (7.67)</td><td headers="hd_h_ml116.t3_1_1_1_2 hd_h_ml116.t3_1_1_2_14" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Active (1.61)</td><td headers="hd_h_ml116.t3_1_1_1_2 hd_h_ml116.t3_1_1_2_15" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Inactive (>55.7)</td><td headers="hd_h_ml116.t3_1_1_1_3 hd_h_ml116.t3_1_1_2_16" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Active (4.2)</td><td headers="hd_h_ml116.t3_1_1_1_3 hd_h_ml116.t3_1_1_2_17" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Inactive (>56)</td><td headers="hd_h_ml116.t3_1_1_1_3 hd_h_ml116.t3_1_1_2_18" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Non-toxic (81.2% viability at 56 μM)</td><td headers="hd_h_ml116.t3_1_1_1_3 hd_h_ml116.t3_1_1_2_19" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Active</td></tr><tr><td headers="hd_h_ml116.t3_1_1_1_1 hd_h_ml116.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>Analog 1</b></td><td headers="hd_h_ml116.t3_1_1_1_1 hd_h_ml116.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SR- 03000000949</td><td headers="hd_h_ml116.t3_1_1_1_1 hd_h_ml116.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK56232/bin/ml116fu10.jpg" alt="Image ml116fu10.jpg" /></div></td><td headers="hd_h_ml116.t3_1_1_1_1 hd_h_ml116.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">41724711</td><td headers="hd_h_ml116.t3_1_1_1_1 hd_h_ml116.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/81080223" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">81080223</a></td><td headers="hd_h_ml116.t3_1_1_1_1 hd_h_ml116.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS002473459</td><td headers="hd_h_ml116.t3_1_1_1_1 hd_h_ml116.t3_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">TSRI</td><td headers="hd_h_ml116.t3_1_1_1_1 hd_h_ml116.t3_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SR- 03000000949</td><td headers="hd_h_ml116.t3_1_1_1_2 hd_h_ml116.t3_1_1_2_9 hd_h_ml116.t3_1_1_2_10 hd_h_ml116.t3_1_1_2_11 hd_h_ml116.t3_1_1_2_12 hd_h_ml116.t3_1_1_2_13 hd_h_ml116.t3_1_1_2_14 hd_h_ml116.t3_1_1_2_15" colspan="7" rowspan="4" style="text-align:center;vertical-align:middle;">These compounds were not in the MLSMR collection</td><td headers="hd_h_ml116.t3_1_1_1_3 hd_h_ml116.t3_1_1_2_16" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Active (0.839)</td><td headers="hd_h_ml116.t3_1_1_1_3 hd_h_ml116.t3_1_1_2_17" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Inactive (>56)</td><td headers="hd_h_ml116.t3_1_1_1_3 hd_h_ml116.t3_1_1_2_18 hd_h_ml116.t3_1_1_2_19" colspan="2" rowspan="4" style="text-align:center;vertical-align:middle;">See below<sup>#</sup></td></tr><tr><td headers="hd_h_ml116.t3_1_1_1_1 hd_h_ml116.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>Analog 2</b></td><td headers="hd_h_ml116.t3_1_1_1_1 hd_h_ml116.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SR- 03000000948</td><td headers="hd_h_ml116.t3_1_1_1_1 hd_h_ml116.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK56232/bin/ml116fu11.jpg" alt="Image ml116fu11.jpg" /></div></td><td headers="hd_h_ml116.t3_1_1_1_1 hd_h_ml116.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">42640809</td><td headers="hd_h_ml116.t3_1_1_1_1 hd_h_ml116.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/81080222" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">81080222</a></td><td headers="hd_h_ml116.t3_1_1_1_1 hd_h_ml116.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS002473458</td><td headers="hd_h_ml116.t3_1_1_1_1 hd_h_ml116.t3_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">TSRI</td><td headers="hd_h_ml116.t3_1_1_1_1 hd_h_ml116.t3_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SR- 03000000948</td><td headers="hd_h_ml116.t3_1_1_1_3 hd_h_ml116.t3_1_1_2_16" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Active (1.69)</td><td headers="hd_h_ml116.t3_1_1_1_3 hd_h_ml116.t3_1_1_2_17" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Inactive (>56)</td></tr><tr><td headers="hd_h_ml116.t3_1_1_1_1 hd_h_ml116.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>Analog 3</b></td><td headers="hd_h_ml116.t3_1_1_1_1 hd_h_ml116.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SR- 03000000947</td><td headers="hd_h_ml116.t3_1_1_1_1 hd_h_ml116.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK56232/bin/ml116fu12.jpg" alt="Image ml116fu12.jpg" /></div></td><td headers="hd_h_ml116.t3_1_1_1_1 hd_h_ml116.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">42640808</td><td headers="hd_h_ml116.t3_1_1_1_1 hd_h_ml116.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/81080221" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">81080221</a></td><td headers="hd_h_ml116.t3_1_1_1_1 hd_h_ml116.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS002473457</td><td headers="hd_h_ml116.t3_1_1_1_1 hd_h_ml116.t3_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">TSRI</td><td headers="hd_h_ml116.t3_1_1_1_1 hd_h_ml116.t3_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SR- 03000000947</td><td headers="hd_h_ml116.t3_1_1_1_3 hd_h_ml116.t3_1_1_2_16" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Active (2.53)</td><td headers="hd_h_ml116.t3_1_1_1_3 hd_h_ml116.t3_1_1_2_17" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Inactive (>56)</td></tr><tr><td headers="hd_h_ml116.t3_1_1_1_1 hd_h_ml116.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>Analog 4</b></td><td headers="hd_h_ml116.t3_1_1_1_1 hd_h_ml116.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SR- 03000001009</td><td headers="hd_h_ml116.t3_1_1_1_1 hd_h_ml116.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK56232/bin/ml116fu13.jpg" alt="Image ml116fu13.jpg" /></div></td><td headers="hd_h_ml116.t3_1_1_1_1 hd_h_ml116.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">44141938</td><td headers="hd_h_ml116.t3_1_1_1_1 hd_h_ml116.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85145925" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85145925</a></td><td headers="hd_h_ml116.t3_1_1_1_1 hd_h_ml116.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS002473641</td><td headers="hd_h_ml116.t3_1_1_1_1 hd_h_ml116.t3_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">TSRI</td><td headers="hd_h_ml116.t3_1_1_1_1 hd_h_ml116.t3_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SR- 03000001009</td><td headers="hd_h_ml116.t3_1_1_1_3 hd_h_ml116.t3_1_1_2_16" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Active (0.837)</td><td headers="hd_h_ml116.t3_1_1_1_3 hd_h_ml116.t3_1_1_2_17" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Inactive (>56)</td></tr><tr><td headers="hd_h_ml116.t3_1_1_1_1 hd_h_ml116.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>Analog 5</b></td><td headers="hd_h_ml116.t3_1_1_1_1 hd_h_ml116.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SR- 01000309219</td><td headers="hd_h_ml116.t3_1_1_1_1 hd_h_ml116.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK56232/bin/ml116fu14.jpg" alt="Image ml116fu14.jpg" /></div></td><td headers="hd_h_ml116.t3_1_1_1_1 hd_h_ml116.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1478199</td><td headers="hd_h_ml116.t3_1_1_1_1 hd_h_ml116.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/24824606" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">24824606</a></td><td headers="hd_h_ml116.t3_1_1_1_1 hd_h_ml116.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS000736205</td><td headers="hd_h_ml116.t3_1_1_1_1 hd_h_ml116.t3_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Key Organics</td><td headers="hd_h_ml116.t3_1_1_1_1 hd_h_ml116.t3_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4X-0840</td><td headers="hd_h_ml116.t3_1_1_1_2 hd_h_ml116.t3_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Inactive (−2.9)</td><td headers="hd_h_ml116.t3_1_1_1_2 hd_h_ml116.t3_1_1_2_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Inactive (−3.7)</td><td headers="hd_h_ml116.t3_1_1_1_2 hd_h_ml116.t3_1_1_2_11 hd_h_ml116.t3_1_1_2_12 hd_h_ml116.t3_1_1_2_13 hd_h_ml116.t3_1_1_2_14 hd_h_ml116.t3_1_1_2_15 hd_h_ml116.t3_1_1_1_3 hd_h_ml116.t3_1_1_2_16 hd_h_ml116.t3_1_1_2_17 hd_h_ml116.t3_1_1_2_18 hd_h_ml116.t3_1_1_2_19" colspan="9" rowspan="1" style="text-align:center;vertical-align:middle;">See below<sup>*</sup></td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>#</dt><dd><div id="ml116.tfn5"><p class="no_margin">These compounds were not tested due to higher off-target activity, compared to probe.</p></div></dd></dl><dl class="bkr_refwrap"><dt>*</dt><dd><div id="ml116.tfn6"><p class="no_margin">This compound was not tested due to inactivity in the Primary screen.</p></div></dd></dl><dl class="bkr_refwrap"><dt>^</dt><dd><div id="ml116.tfn7"><p class="no_margin">This compound was not tested due to non-selectivity as determined by the Assay Provider (PMID 18824601).</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobml116t4"><div id="ml116.t4" class="table"><h3><span class="label">SAR Table 2</span><span class="title">Additional synthesized and purchased analogs</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK56232/table/ml116.t4/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml116.t4_lrgtbl__"><table class="no_margin"><thead><tr><th id="hd_h_ml116.t4_1_1_1_1" colspan="8" rowspan="1" style="text-align:center;vertical-align:middle;">Compound Information</th><th id="hd_h_ml116.t4_1_1_1_2" colspan="7" rowspan="1" style="text-align:center;vertical-align:middle;">Screening Assays</th><th id="hd_h_ml116.t4_1_1_1_3" colspan="4" rowspan="1" style="text-align:center;vertical-align:middle;">Probe Development (AIDs <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1806" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1806</a> and <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2078" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2078</a>)</th></tr><tr><th headers="hd_h_ml116.t4_1_1_1_1" id="hd_h_ml116.t4_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Compound</th><th headers="hd_h_ml116.t4_1_1_1_1" id="hd_h_ml116.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SR-Number</th><th headers="hd_h_ml116.t4_1_1_1_1" id="hd_h_ml116.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Structure</th><th headers="hd_h_ml116.t4_1_1_1_1" id="hd_h_ml116.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID</th><th headers="hd_h_ml116.t4_1_1_1_1" id="hd_h_ml116.t4_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SID</th><th headers="hd_h_ml116.t4_1_1_1_1" id="hd_h_ml116.t4_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS ID</th><th headers="hd_h_ml116.t4_1_1_1_1" id="hd_h_ml116.t4_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Vendor</th><th headers="hd_h_ml116.t4_1_1_1_1" id="hd_h_ml116.t4_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Vendor Catalog ID</th><th headers="hd_h_ml116.t4_1_1_1_2" id="hd_h_ml116.t4_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">STAT3 Primary (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/862" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-862</a>: %INH)</th><th headers="hd_h_ml116.t4_1_1_1_2" id="hd_h_ml116.t4_1_1_2_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">STAT1 Primary (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/920" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-920</a>: %INH)</th><th headers="hd_h_ml116.t4_1_1_1_2" id="hd_h_ml116.t4_1_1_2_11" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">STAT3 Confirmation (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1265" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1265</a>: %INH)</th><th headers="hd_h_ml116.t4_1_1_1_2" id="hd_h_ml116.t4_1_1_2_12" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NFkB (3X Counterscreen (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1308" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1308</a>: %INH)</th><th headers="hd_h_ml116.t4_1_1_1_2" id="hd_h_ml116.t4_1_1_2_13" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">STAT1 (3X Counterscreen (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1317" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1317</a>: %INH)</th><th headers="hd_h_ml116.t4_1_1_1_2" id="hd_h_ml116.t4_1_1_2_14" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">STAT3 Dose Response (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1399" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1399</a>: IC50, μM)</th><th headers="hd_h_ml116.t4_1_1_1_2" id="hd_h_ml116.t4_1_1_2_15" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">STAT1 Dose Response Counterscreen (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1411" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1411</a>: IC50, μM)</th><th headers="hd_h_ml116.t4_1_1_1_3" id="hd_h_ml116.t4_1_1_2_16" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">STAT3 IC50 (μM)</th><th headers="hd_h_ml116.t4_1_1_1_3" id="hd_h_ml116.t4_1_1_2_17" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">STAT1 IC50 (μM)</th><th headers="hd_h_ml116.t4_1_1_1_3" id="hd_h_ml116.t4_1_1_2_18" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Cytotoxicity Assay</th><th headers="hd_h_ml116.t4_1_1_1_3" id="hd_h_ml116.t4_1_1_2_19" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">qPCR Assay</th></tr></thead><tbody><tr><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>Analog 6</b></td><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SR- 03000000876</td><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK56232/bin/ml116fu15.jpg" alt="Image ml116fu15.jpg" /></div></td><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">675430</td><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/57288075" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">57288075</a></td><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">None</td><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Princeton BioMolecular</td><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">OSSK_852766</td><td headers="hd_h_ml116.t4_1_1_1_2 hd_h_ml116.t4_1_1_2_9 hd_h_ml116.t4_1_1_2_10 hd_h_ml116.t4_1_1_2_11 hd_h_ml116.t4_1_1_2_12 hd_h_ml116.t4_1_1_2_13 hd_h_ml116.t4_1_1_2_14 hd_h_ml116.t4_1_1_2_15" colspan="7" rowspan="2" style="text-align:center;vertical-align:middle;">These compounds were not in the MLSMR collection</td><td headers="hd_h_ml116.t4_1_1_1_3 hd_h_ml116.t4_1_1_2_16" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Inactive (20)</td><td headers="hd_h_ml116.t4_1_1_1_3 hd_h_ml116.t4_1_1_2_17" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Inactive (>56)</td><td headers="hd_h_ml116.t4_1_1_1_3 hd_h_ml116.t4_1_1_2_18 hd_h_ml116.t4_1_1_2_19" colspan="2" rowspan="8" style="text-align:center;vertical-align:middle;">See below<sup>†</sup></td></tr><tr><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>Analog 7</b></td><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SR- 03000000838</td><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK56232/bin/ml116fu16.jpg" alt="Image ml116fu16.jpg" /></div></td><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">16582798</td><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/57288040" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">57288040</a></td><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">None</td><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">UkrOrgSyn thesis</td><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">PB221597938</td><td headers="hd_h_ml116.t4_1_1_1_3 hd_h_ml116.t4_1_1_2_16" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Inactive (5.21)</td><td headers="hd_h_ml116.t4_1_1_1_3 hd_h_ml116.t4_1_1_2_17" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Inactive (>56)</td></tr><tr><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>Analog 8</b></td><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SR- 01000307211</td><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK56232/bin/ml116fu17.jpg" alt="Image ml116fu17.jpg" /></div></td><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1478208</td><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/57287832" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">57287832</a></td><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS000720742</td><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Key Organics</td><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4X-0850</td><td headers="hd_h_ml116.t4_1_1_1_2 hd_h_ml116.t4_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Inactive (24.5%)</td><td headers="hd_h_ml116.t4_1_1_1_2 hd_h_ml116.t4_1_1_2_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Inactive (22.17%)</td><td headers="hd_h_ml116.t4_1_1_1_2 hd_h_ml116.t4_1_1_2_11 hd_h_ml116.t4_1_1_2_12 hd_h_ml116.t4_1_1_2_13 hd_h_ml116.t4_1_1_2_14 hd_h_ml116.t4_1_1_2_15" colspan="5" rowspan="1" style="text-align:center;vertical-align:middle;">See below<sup>*</sup></td><td headers="hd_h_ml116.t4_1_1_1_3 hd_h_ml116.t4_1_1_2_16" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Inactive (13.7)</td><td headers="hd_h_ml116.t4_1_1_1_3 hd_h_ml116.t4_1_1_2_17" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Inactive (>56)</td></tr><tr><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>Analog 9</b></td><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SR- 03000000836</td><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK56232/bin/ml116fu18.jpg" alt="Image ml116fu18.jpg" /></div></td><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2012886</td><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/57288038" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">57288038</a></td><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">None</td><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Enamine</td><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">T5751803</td><td headers="hd_h_ml116.t4_1_1_1_2 hd_h_ml116.t4_1_1_2_9 hd_h_ml116.t4_1_1_2_10 hd_h_ml116.t4_1_1_2_11 hd_h_ml116.t4_1_1_2_12 hd_h_ml116.t4_1_1_2_13 hd_h_ml116.t4_1_1_2_14 hd_h_ml116.t4_1_1_2_15" colspan="7" rowspan="5" style="text-align:center;vertical-align:middle;">These compounds were not in the MLSMR collection</td><td headers="hd_h_ml116.t4_1_1_1_3 hd_h_ml116.t4_1_1_2_16" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Inactive (16.7)</td><td headers="hd_h_ml116.t4_1_1_1_3 hd_h_ml116.t4_1_1_2_17" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Inactive (>56)</td></tr><tr><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>Analog 10</b></td><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SR- 03000000830</td><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK56232/bin/ml116fu19.jpg" alt="Image ml116fu19.jpg" /></div></td><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2238888</td><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/57288032" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">57288032</a></td><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">None</td><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Enamine</td><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">ZT- 2781134</td><td headers="hd_h_ml116.t4_1_1_1_3 hd_h_ml116.t4_1_1_2_16" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Inactive (>18.6 )</td><td headers="hd_h_ml116.t4_1_1_1_3 hd_h_ml116.t4_1_1_2_17" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Inactive (>56)</td></tr><tr><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>Analog 11</b></td><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SR- 01000307258</td><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK56232/bin/ml116fu20.jpg" alt="Image ml116fu20.jpg" /></div></td><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1478193</td><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/57287833" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">57287833</a></td><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">None</td><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Key Organics</td><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4X-0832</td><td headers="hd_h_ml116.t4_1_1_1_3 hd_h_ml116.t4_1_1_2_16" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Inactive (>18.6 )</td><td headers="hd_h_ml116.t4_1_1_1_3 hd_h_ml116.t4_1_1_2_17" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Inactive (>56)</td></tr><tr><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>Analog 12</b></td><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SR- 03000000835</td><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK56232/bin/ml116fu21.jpg" alt="Image ml116fu21.jpg" /></div></td><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">25181300</td><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/57288037" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">57288037</a></td><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">None</td><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Enamine</td><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Z128135924</td><td headers="hd_h_ml116.t4_1_1_1_3 hd_h_ml116.t4_1_1_2_16" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Inactive (>18.6 )</td><td headers="hd_h_ml116.t4_1_1_1_3 hd_h_ml116.t4_1_1_2_17" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Inactive (>56)</td></tr><tr><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>Analog 13</b></td><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SR- 03000000840</td><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK56232/bin/ml116fu22.jpg" alt="Image ml116fu22.jpg" /></div></td><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2241376</td><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/57288042" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">57288042</a></td><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">None</td><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Enamine</td><td headers="hd_h_ml116.t4_1_1_1_1 hd_h_ml116.t4_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">T5890287</td><td headers="hd_h_ml116.t4_1_1_1_3 hd_h_ml116.t4_1_1_2_16" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Inactive (>56)</td><td headers="hd_h_ml116.t4_1_1_1_3 hd_h_ml116.t4_1_1_2_17" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Inactive (>56)</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>*</dt><dd><div id="ml116.tfn8"><p class="no_margin">This compound was not tested due to inactivity in the Primary screen.</p></div></dd></dl><dl class="bkr_refwrap"><dt>†</dt><dd><div id="ml116.tfn9"><p class="no_margin">These compounds were not tested due to lower target potency, compared to probe.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobml116t5"><div id="ml116.t5" class="table"><h3><span class="label">SAR Table 3</span><span class="title">Additional synthesized and purchased analogs</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK56232/table/ml116.t5/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml116.t5_lrgtbl__"><table class="no_margin"><thead><tr><th id="hd_h_ml116.t5_1_1_1_1" colspan="8" rowspan="1" style="text-align:center;vertical-align:middle;">Compound Information</th><th id="hd_h_ml116.t5_1_1_1_2" colspan="7" rowspan="1" style="text-align:center;vertical-align:middle;">Screening Assays</th><th id="hd_h_ml116.t5_1_1_1_3" colspan="4" rowspan="1" style="text-align:center;vertical-align:middle;">Probe Development (AIDs <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1806" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1806</a> and <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2078" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2078</a>)</th></tr><tr><th headers="hd_h_ml116.t5_1_1_1_1" id="hd_h_ml116.t5_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Compound</th><th headers="hd_h_ml116.t5_1_1_1_1" id="hd_h_ml116.t5_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SR-Number</th><th headers="hd_h_ml116.t5_1_1_1_1" id="hd_h_ml116.t5_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Structure</th><th headers="hd_h_ml116.t5_1_1_1_1" id="hd_h_ml116.t5_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID</th><th headers="hd_h_ml116.t5_1_1_1_1" id="hd_h_ml116.t5_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SID</th><th headers="hd_h_ml116.t5_1_1_1_1" id="hd_h_ml116.t5_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS ID</th><th headers="hd_h_ml116.t5_1_1_1_1" id="hd_h_ml116.t5_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Vendor</th><th headers="hd_h_ml116.t5_1_1_1_1" id="hd_h_ml116.t5_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Vendor Catalog ID</th><th headers="hd_h_ml116.t5_1_1_1_2" id="hd_h_ml116.t5_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">STAT3 Primary (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/862" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-862</a>: %INH)</th><th headers="hd_h_ml116.t5_1_1_1_2" id="hd_h_ml116.t5_1_1_2_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">STAT1 Primary (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/920" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-920</a>: %INH)</th><th headers="hd_h_ml116.t5_1_1_1_2" id="hd_h_ml116.t5_1_1_2_11" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">STAT3 Confirmation (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1265" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1265</a>: %INH)</th><th headers="hd_h_ml116.t5_1_1_1_2" id="hd_h_ml116.t5_1_1_2_12" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NFkB (3X Counterscreen (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1308" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1308</a>: %INH)</th><th headers="hd_h_ml116.t5_1_1_1_2" id="hd_h_ml116.t5_1_1_2_13" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">STAT1 (3X Counterscreen (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1317" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1317</a>: %INH)</th><th headers="hd_h_ml116.t5_1_1_1_2" id="hd_h_ml116.t5_1_1_2_14" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">STAT3 Dose Response (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1399" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1399</a>: IC50, μM)</th><th headers="hd_h_ml116.t5_1_1_1_2" id="hd_h_ml116.t5_1_1_2_15" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">STAT1 Dose Response Counterscreen (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1411" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1411</a>: IC50, μM)</th><th headers="hd_h_ml116.t5_1_1_1_3" id="hd_h_ml116.t5_1_1_2_16" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">STAT3 IC50 (μM)</th><th headers="hd_h_ml116.t5_1_1_1_3" id="hd_h_ml116.t5_1_1_2_17" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">STAT1 IC50 (μM)</th><th headers="hd_h_ml116.t5_1_1_1_3" id="hd_h_ml116.t5_1_1_2_18" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Cytotoxicity Assay</th><th headers="hd_h_ml116.t5_1_1_1_3" id="hd_h_ml116.t5_1_1_2_19" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">qPCR Assay</th></tr></thead><tbody><tr><td headers="hd_h_ml116.t5_1_1_1_1 hd_h_ml116.t5_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>Analog 14</b></td><td headers="hd_h_ml116.t5_1_1_1_1 hd_h_ml116.t5_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SR- 01000410943</td><td headers="hd_h_ml116.t5_1_1_1_1 hd_h_ml116.t5_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK56232/bin/ml116fu23.jpg" alt="Image ml116fu23.jpg" /></div></td><td headers="hd_h_ml116.t5_1_1_1_1 hd_h_ml116.t5_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">403054</td><td headers="hd_h_ml116.t5_1_1_1_1 hd_h_ml116.t5_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/57287838" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">57287838</a></td><td headers="hd_h_ml116.t5_1_1_1_1 hd_h_ml116.t5_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">None</td><td headers="hd_h_ml116.t5_1_1_1_1 hd_h_ml116.t5_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Innovapharm Ltd.</td><td headers="hd_h_ml116.t5_1_1_1_1 hd_h_ml116.t5_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">STT- 00083650</td><td headers="hd_h_ml116.t5_1_1_1_2 hd_h_ml116.t5_1_1_2_9 hd_h_ml116.t5_1_1_2_10 hd_h_ml116.t5_1_1_2_11 hd_h_ml116.t5_1_1_2_12 hd_h_ml116.t5_1_1_2_13 hd_h_ml116.t5_1_1_2_14 hd_h_ml116.t5_1_1_2_15" colspan="7" rowspan="7" style="text-align:center;vertical-align:middle;">These compounds were not in the MLSMR collection.</td><td headers="hd_h_ml116.t5_1_1_1_3 hd_h_ml116.t5_1_1_2_16" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Inactive (>56)</td><td headers="hd_h_ml116.t5_1_1_1_3 hd_h_ml116.t5_1_1_2_17" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Inactive (>56)</td><td headers="hd_h_ml116.t5_1_1_1_3 hd_h_ml116.t5_1_1_2_18 hd_h_ml116.t5_1_1_2_19" colspan="2" rowspan="7" style="text-align:center;vertical-align:middle;">See below <sup>†</sup></td></tr><tr><td headers="hd_h_ml116.t5_1_1_1_1 hd_h_ml116.t5_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>Analog 15</b></td><td headers="hd_h_ml116.t5_1_1_1_1 hd_h_ml116.t5_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SR- 01000468078</td><td headers="hd_h_ml116.t5_1_1_1_1 hd_h_ml116.t5_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK56232/bin/ml116fu24.jpg" alt="Image ml116fu24.jpg" /></div></td><td headers="hd_h_ml116.t5_1_1_1_1 hd_h_ml116.t5_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">22330557</td><td headers="hd_h_ml116.t5_1_1_1_1 hd_h_ml116.t5_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/57287843" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">57287843</a></td><td headers="hd_h_ml116.t5_1_1_1_1 hd_h_ml116.t5_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">None</td><td headers="hd_h_ml116.t5_1_1_1_1 hd_h_ml116.t5_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">ChemDiv</td><td headers="hd_h_ml116.t5_1_1_1_1 hd_h_ml116.t5_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3909-8202</td><td headers="hd_h_ml116.t5_1_1_1_3 hd_h_ml116.t5_1_1_2_16" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Inactive (>56)</td><td headers="hd_h_ml116.t5_1_1_1_3 hd_h_ml116.t5_1_1_2_17" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Inactive (>56)</td></tr><tr><td headers="hd_h_ml116.t5_1_1_1_1 hd_h_ml116.t5_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>Analog 16</b></td><td headers="hd_h_ml116.t5_1_1_1_1 hd_h_ml116.t5_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SR- 03000000834</td><td headers="hd_h_ml116.t5_1_1_1_1 hd_h_ml116.t5_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK56232/bin/ml116fu25.jpg" alt="Image ml116fu25.jpg" /></div></td><td headers="hd_h_ml116.t5_1_1_1_1 hd_h_ml116.t5_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2461091</td><td headers="hd_h_ml116.t5_1_1_1_1 hd_h_ml116.t5_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/57288036" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">57288036</a></td><td headers="hd_h_ml116.t5_1_1_1_1 hd_h_ml116.t5_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">None</td><td headers="hd_h_ml116.t5_1_1_1_1 hd_h_ml116.t5_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Enamine</td><td headers="hd_h_ml116.t5_1_1_1_1 hd_h_ml116.t5_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">T0518-5756</td><td headers="hd_h_ml116.t5_1_1_1_3 hd_h_ml116.t5_1_1_2_16" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Inactive (>56)</td><td headers="hd_h_ml116.t5_1_1_1_3 hd_h_ml116.t5_1_1_2_17" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Inactive (>56)</td></tr><tr><td headers="hd_h_ml116.t5_1_1_1_1 hd_h_ml116.t5_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>Analog 17</b></td><td headers="hd_h_ml116.t5_1_1_1_1 hd_h_ml116.t5_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SR- 03000000839</td><td headers="hd_h_ml116.t5_1_1_1_1 hd_h_ml116.t5_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK56232/bin/ml116fu26.jpg" alt="Image ml116fu26.jpg" /></div></td><td headers="hd_h_ml116.t5_1_1_1_1 hd_h_ml116.t5_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">25181302</td><td headers="hd_h_ml116.t5_1_1_1_1 hd_h_ml116.t5_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/57288041" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">57288041</a></td><td headers="hd_h_ml116.t5_1_1_1_1 hd_h_ml116.t5_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">None</td><td headers="hd_h_ml116.t5_1_1_1_1 hd_h_ml116.t5_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Enamine</td><td headers="hd_h_ml116.t5_1_1_1_1 hd_h_ml116.t5_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">T5949401</td><td headers="hd_h_ml116.t5_1_1_1_3 hd_h_ml116.t5_1_1_2_16" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Inactive (>56)</td><td headers="hd_h_ml116.t5_1_1_1_3 hd_h_ml116.t5_1_1_2_17" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Inactive (>56)</td></tr><tr><td headers="hd_h_ml116.t5_1_1_1_1 hd_h_ml116.t5_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>Analog 18</b></td><td headers="hd_h_ml116.t5_1_1_1_1 hd_h_ml116.t5_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SR- 03000000833</td><td headers="hd_h_ml116.t5_1_1_1_1 hd_h_ml116.t5_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK56232/bin/ml116fu27.jpg" alt="Image ml116fu27.jpg" /></div></td><td headers="hd_h_ml116.t5_1_1_1_1 hd_h_ml116.t5_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2383960</td><td headers="hd_h_ml116.t5_1_1_1_1 hd_h_ml116.t5_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/57288035" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">57288035</a></td><td headers="hd_h_ml116.t5_1_1_1_1 hd_h_ml116.t5_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">None</td><td headers="hd_h_ml116.t5_1_1_1_1 hd_h_ml116.t5_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Enamine</td><td headers="hd_h_ml116.t5_1_1_1_1 hd_h_ml116.t5_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">T0513-7859</td><td headers="hd_h_ml116.t5_1_1_1_3 hd_h_ml116.t5_1_1_2_16" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Inactive (>56)</td><td headers="hd_h_ml116.t5_1_1_1_3 hd_h_ml116.t5_1_1_2_17" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Inactive (>56)</td></tr><tr><td headers="hd_h_ml116.t5_1_1_1_1 hd_h_ml116.t5_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>Analog 19</b></td><td headers="hd_h_ml116.t5_1_1_1_1 hd_h_ml116.t5_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SR- 03000000961</td><td headers="hd_h_ml116.t5_1_1_1_1 hd_h_ml116.t5_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK56232/bin/ml116fu28.jpg" alt="Image ml116fu28.jpg" /></div></td><td headers="hd_h_ml116.t5_1_1_1_1 hd_h_ml116.t5_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">17415585</td><td headers="hd_h_ml116.t5_1_1_1_1 hd_h_ml116.t5_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85281103" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85281103</a></td><td headers="hd_h_ml116.t5_1_1_1_1 hd_h_ml116.t5_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">None</td><td headers="hd_h_ml116.t5_1_1_1_1 hd_h_ml116.t5_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Enamine</td><td headers="hd_h_ml116.t5_1_1_1_1 hd_h_ml116.t5_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">T5746186</td><td headers="hd_h_ml116.t5_1_1_1_3 hd_h_ml116.t5_1_1_2_16" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Inactive (>18.6 )</td><td headers="hd_h_ml116.t5_1_1_1_3 hd_h_ml116.t5_1_1_2_17" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Inactive (>56)</td></tr><tr><td headers="hd_h_ml116.t5_1_1_1_1 hd_h_ml116.t5_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>Analog 20</b></td><td headers="hd_h_ml116.t5_1_1_1_1 hd_h_ml116.t5_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SR- 03000000966</td><td headers="hd_h_ml116.t5_1_1_1_1 hd_h_ml116.t5_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK56232/bin/ml116fu29.jpg" alt="Image ml116fu29.jpg" /></div></td><td headers="hd_h_ml116.t5_1_1_1_1 hd_h_ml116.t5_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">24620995</td><td headers="hd_h_ml116.t5_1_1_1_1 hd_h_ml116.t5_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85281104" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85281104</a></td><td headers="hd_h_ml116.t5_1_1_1_1 hd_h_ml116.t5_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">None</td><td headers="hd_h_ml116.t5_1_1_1_1 hd_h_ml116.t5_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Enamine</td><td headers="hd_h_ml116.t5_1_1_1_1 hd_h_ml116.t5_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">T6328260</td><td headers="hd_h_ml116.t5_1_1_1_3 hd_h_ml116.t5_1_1_2_16" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Active (1.84)</td><td headers="hd_h_ml116.t5_1_1_1_3 hd_h_ml116.t5_1_1_2_17" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Inactive (>56)</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>†</dt><dd><div id="ml116.tfn10"><p class="no_margin">These compounds were not tested due to lower target potency, compared to probe.</p></div></dd></dl></dl></div></div></div></article><article data-type="fig" id="figobml116fu7"><div id="ml116.fu7" class="figure"><div class="graphic"><img data-src="/books/NBK56232/bin/ml116fu30.jpg" alt="Image ml116fu30" /></div></div></article><article data-type="fig" id="figobml116fu8"><div id="ml116.fu8" class="figure"><div class="graphic"><img data-src="/books/NBK56232/bin/ml116fu31.jpg" alt="Image ml116fu31" /></div></div></article><article data-type="table-wrap" id="figobml116tu6"><div id="ml116.tu6" class="table"><h3><span class="title">Comparative Activity Table: Probe and Prior Art Compounds</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK56232/table/ml116.tu6/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml116.tu6_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml116.tu6_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Compound</th><th id="hd_h_ml116.tu6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Structure</th><th id="hd_h_ml116.tu6_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID</th><th id="hd_h_ml116.tu6_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CAS #</th><th id="hd_h_ml116.tu6_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">STAT3 IC50</th><th id="hd_h_ml116.tu6_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">STAT1 IC50</th><th id="hd_h_ml116.tu6_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">PubChem Activity Profile</th><th id="hd_h_ml116.tu6_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Selectivity</th><th id="hd_h_ml116.tu6_1_1_1_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">PMID</th></tr></thead><tbody><tr><td headers="hd_h_ml116.tu6_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Probe <a href="/pcsubstance/?term=ML116[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML116</a></td><td headers="hd_h_ml116.tu6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK56232/bin/ml116fu32.jpg" alt="Image ml116fu32.jpg" /></div></td><td headers="hd_h_ml116.tu6_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2100018</td><td headers="hd_h_ml116.tu6_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">None</td><td headers="hd_h_ml116.tu6_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4.2 μM</td><td headers="hd_h_ml116.tu6_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Inactive (>56 μM)</td><td headers="hd_h_ml116.tu6_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">17 of 270 (6.3%)</td><td headers="hd_h_ml116.tu6_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">STAT3 Selective</td><td headers="hd_h_ml116.tu6_1_1_1_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Pending</td></tr><tr><td headers="hd_h_ml116.tu6_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Prior art Stattic</td><td headers="hd_h_ml116.tu6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK56232/bin/ml116fu33.jpg" alt="Image ml116fu33.jpg" /></div></td><td headers="hd_h_ml116.tu6_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2779853</td><td headers="hd_h_ml116.tu6_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">19983-44-9</td><td headers="hd_h_ml116.tu6_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>4–6 μM</td><td headers="hd_h_ml116.tu6_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Active (4–6 μM)</td><td headers="hd_h_ml116.tu6_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3 of 44 (6.8%)</td><td headers="hd_h_ml116.tu6_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Non- selective</td><td headers="hd_h_ml116.tu6_1_1_1_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20576164 (see Fig 4B)</td></tr><tr><td headers="hd_h_ml116.tu6_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Prior art Nifuroxazide (oral nitrofuran antibiotic)</td><td headers="hd_h_ml116.tu6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK56232/bin/ml116fu34.jpg" alt="Image ml116fu34.jpg" /></div></td><td headers="hd_h_ml116.tu6_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5337997</td><td headers="hd_h_ml116.tu6_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">965-52-6</td><td headers="hd_h_ml116.tu6_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3 μM (IC50 = 8.34 μM when tested by Scripps)</td><td headers="hd_h_ml116.tu6_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Active against STAT1 and STAT5</td><td headers="hd_h_ml116.tu6_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2 of 20 (10%)</td><td headers="hd_h_ml116.tu6_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Non- selective</td><td headers="hd_h_ml116.tu6_1_1_1_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">18824601</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobml116fu9"><div id="ml116.fu9" class="figure"><div class="graphic"><img data-src="/books/NBK56232/bin/ml116fu35.jpg" alt="Image ml116fu35" /></div></div></article></div><div id="jr-scripts"><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/libs.min.js"> </script><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.min.js"> </script></div></div>
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