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<meta name="robots" content="INDEX,FOLLOW,NOARCHIVE" /><meta name="citation_inbook_title" content="Probe Reports from the NIH Molecular Libraries Program [Internet]" /><meta name="citation_title" content="Therapeutic Inhibitors of Phosphomannose Isomerase - Probe 1" /><meta name="citation_publisher" content="National Center for Biotechnology Information (US)" /><meta name="citation_date" content="2010/09/02" /><meta name="citation_author" content="Michael Hedrick" /><meta name="citation_author" content="Brock Brown" /><meta name="citation_author" content="Justin Rascon" /><meta name="citation_author" content="Eduard Sergienko" /><meta name="citation_author" content="Vandana Sharma" /><meta name="citation_author" content="Bobby Ng" /><meta name="citation_author" content="Mie Ichikawa" /><meta name="citation_author" content="Hudson Freeze" /><meta name="citation_author" content="Derek Stonich" /><meta name="citation_author" content="Ying Su" /><meta name="citation_author" content="Thomas DY Chung" /><meta name="citation_author" content="Russell Dahl" /><meta name="citation_author" content="Nick Cosford" /><meta name="citation_pmid" content="21433361" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK47345/" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="Therapeutic Inhibitors of Phosphomannose Isomerase - Probe 1" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="National Center for Biotechnology Information (US)" /><meta name="DC.Contributor" content="Michael Hedrick" /><meta name="DC.Contributor" content="Brock Brown" /><meta name="DC.Contributor" content="Justin Rascon" /><meta name="DC.Contributor" content="Eduard Sergienko" /><meta name="DC.Contributor" content="Vandana Sharma" /><meta name="DC.Contributor" content="Bobby Ng" /><meta name="DC.Contributor" content="Mie Ichikawa" /><meta name="DC.Contributor" content="Hudson Freeze" /><meta name="DC.Contributor" content="Derek Stonich" /><meta name="DC.Contributor" content="Ying Su" /><meta name="DC.Contributor" content="Thomas DY Chung" /><meta name="DC.Contributor" content="Russell Dahl" /><meta name="DC.Contributor" content="Nick Cosford" /><meta name="DC.Date" content="2010/09/02" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK47345/" /><meta name="description" content="Type Ia Congenital Disorders of Glycosylation (CDG-Ia) is the most common form of Congenital Disorders of Glycosylation, an autosomal recessive defects in the synthesis of N-linked oligosaccharide chains caused by defects in the PMM2 gene. PMM2 encodes phosphomannomutase 2, which is responsible for the conversion of mannose-6-P [Man-6-P] to Man-1-P. Currently, there is no treatment for CDG-Ia patients. The current project aimed to identify novel non-competitive inhibitors of PMI that can be used as potential therapeutic treatments for these patients. The developed probe ML089 (CID-22416235) inhibits human phosphomannose isomerase (PMI) and may inhibit other PMI orthologs due to the highly conserved nature of the enzyme. The probe is membrane permeable and, as a result ,can also be used to inhibit PMI in living cells. Thus, the probe may serve as a therapeutic treatment for CDG-Ia patients by blocking the catabolism of Man-6-P in cells, thereby redirecting it towards protein glycosylation using this residual PMM2 activity." /><meta name="og:title" content="Therapeutic Inhibitors of Phosphomannose Isomerase - Probe 1" /><meta name="og:type" content="book" /><meta name="og:description" content="Type Ia Congenital Disorders of Glycosylation (CDG-Ia) is the most common form of Congenital Disorders of Glycosylation, an autosomal recessive defects in the synthesis of N-linked oligosaccharide chains caused by defects in the PMM2 gene. PMM2 encodes phosphomannomutase 2, which is responsible for the conversion of mannose-6-P [Man-6-P] to Man-1-P. Currently, there is no treatment for CDG-Ia patients. The current project aimed to identify novel non-competitive inhibitors of PMI that can be used as potential therapeutic treatments for these patients. The developed probe ML089 (CID-22416235) inhibits human phosphomannose isomerase (PMI) and may inhibit other PMI orthologs due to the highly conserved nature of the enzyme. The probe is membrane permeable and, as a result ,can also be used to inhibit PMI in living cells. 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<div class="pre-content"><div><div class="bk_prnt"><p class="small">NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.</p><p>Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010-. </p></div><div class="iconblock clearfix whole_rhythm no_top_margin bk_noprnt"><a class="img_link icnblk_img" title="Table of Contents Page" href="/books/n/mlprobe/"><img class="source-thumb" src="/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-mlprobe-lrg.png" alt="Cover of Probe Reports from the NIH Molecular Libraries Program" height="100px" width="80px" /></a><div class="icnblk_cntnt eight_col"><h2>Probe Reports from the NIH Molecular Libraries Program [Internet].</h2><a data-jig="ncbitoggler" href="#__NBK47345_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK47345_dtls__"><div>Bethesda (MD): National Center for Biotechnology Information (US); 2010-.</div></div><div class="half_rhythm"><ul class="inline_list"><li style="margin-right:1em"><a class="bk_cntns" href="/books/n/mlprobe/">Contents</a></li></ul></div><div class="bk_noprnt"><form method="get" action="/books/n/mlprobe/" id="bk_srch"><div class="bk_search"><label for="bk_term" class="offscreen_noflow">Search term</label><input type="text" title="Search this book" id="bk_term" name="term" value="" data-jig="ncbiclearbutton" /> <input type="submit" class="jig-ncbibutton" value="Search this book" submit="false" style="padding: 0.1em 0.4em;" /></div></form></div></div><div class="icnblk_cntnt two_col"><div class="pagination bk_noprnt"><a class="active page_link prev" href="/books/n/mlprobe/ml090/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/mlprobe/ml088/" title="Next page in this title">Next ></a></div></div></div></div></div>
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<div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><h1 id="_NBK47345_"><span class="title" itemprop="name">Therapeutic Inhibitors of Phosphomannose Isomerase - Probe 1</span></h1><p class="contrib-group"><span itemprop="author">Michael Hedrick</span>, <span itemprop="author">Brock Brown</span>, <span itemprop="author">Justin Rascon</span>, <span itemprop="author">Eduard Sergienko</span>, <span itemprop="author">Vandana Sharma</span>, <span itemprop="author">Bobby Ng</span>, <span itemprop="author">Mie Ichikawa</span>, <span itemprop="author">Hudson Freeze</span>, <span itemprop="author">Derek Stonich</span>, <span itemprop="author">Ying Su</span>, <span itemprop="author">Thomas DY Chung</span>, <span itemprop="author">Russell Dahl</span>, and <span itemprop="author">Nick Cosford</span>.</p><p class="small">Received: <span itemprop="datePublished">April 21, 2009</span>; Last Update: <span itemprop="dateModified">September 2, 2010</span>.</p></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="_abs_rndgid_" itemprop="description"><p>Type Ia Congenital Disorders of Glycosylation (CDG-Ia) is the most common form of Congenital Disorders of Glycosylation, an autosomal recessive defects in the synthesis of N-linked oligosaccharide chains caused by defects in the PMM2 gene. PMM2 encodes phosphomannomutase 2, which is responsible for the conversion of mannose-6-P [Man-6-P] to Man-1-P. Currently, there is no treatment for CDG-Ia patients. The current project aimed to identify novel non-competitive inhibitors of PMI that can be used as potential therapeutic treatments for these patients. The developed probe ML089 (CID-22416235) inhibits human phosphomannose isomerase (PMI) and may inhibit other PMI orthologs due to the highly conserved nature of the enzyme. The probe is membrane permeable and, as a result ,can also be used to inhibit PMI in living cells. Thus, the probe may serve as a therapeutic treatment for CDG-Ia patients by blocking the catabolism of Man-6-P in cells, thereby redirecting it towards protein glycosylation using this residual PMM2 activity.</p></div><div class="h2"></div><p><b>Assigned Assay Grant #:</b> R03 MH082386-01</p><p><b>Screening Center Name & PI:</b>
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<i>Conrad Prebys</i> Center for Chemical Genomics (<i>formerly Burnham Center for Chemical Genomics</i>) & Dr. John C. Reed</p><p><b>Chemistry Center Name & PI:</b>
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<i>Conrad Prebys</i> Center for Chemical Genomics (<i>formerly Burnham Center for Chemical Genomics)</i> & Dr. John C. Reed</p><p><b>Assay Submitter & Institution:</b> Dr. John C Reed & Sanford-Burnham Medical Research Institute (<i>formerly Burnham Institute for Medical Research</i>)</p><p><b>PubChem Summary Bioassay Identifier (AID):</b>
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<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1545" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1545</a></p><div id="ml089.s2"><h2 id="_ml089_s2_">Probe Structure & Characteristics</h2><div id="ml089.fu1" class="figure"><div class="graphic"><img src="/books/NBK47345/bin/ml089fu1.jpg" alt="Image ml089fu1" /></div></div><div id="ml089.tu1" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK47345/table/ml089.tu1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml089.tu1_lrgtbl__"><table><thead><tr><th id="hd_h_ml089.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CID/ML</th><th id="hd_h_ml089.tu1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Target Name</th><th id="hd_h_ml089.tu1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">IC50/EC50 (nM) [SID, AID]</th><th id="hd_h_ml089.tu1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Anti-target Name(s)</th><th id="hd_h_ml089.tu1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">IC50/EC50 (μM) [SID, AID]</th><th id="hd_h_ml089.tu1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Selectivity</th><th id="hd_h_ml089.tu1_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Secondary Assay(s) Name: IC50/EC50 (nM) [SID, AID]</th></tr></thead><tbody><tr><td headers="hd_h_ml089.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CID-22416235<br /><br /><a href="/pcsubstance/?term=ML089[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML089</a></td><td headers="hd_h_ml089.tu1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Phosphomannose<br />Isomerase</td><td headers="hd_h_ml089.tu1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1,300 nM IC50<br /><a href="https://pubchem.ncbi.nlm.nih.gov/substance/57287553" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-57287553</a><br /><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1535" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1535</a></td><td headers="hd_h_ml089.tu1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">PMM2</td><td headers="hd_h_ml089.tu1_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">83 µM IC50<br /><a href="https://pubchem.ncbi.nlm.nih.gov/substance/57287553" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-57287553</a><br /><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1655" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1655</a></td><td headers="hd_h_ml089.tu1_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">69 X</td><td headers="hd_h_ml089.tu1_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">PHOSPHO1<br />800 nM IC50<br /><br /><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1666" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1666</a></td></tr></tbody></table></div></div></div><div id="ml089.s3"><h2 id="_ml089_s3_">Recommendations for the scientific use of this probe</h2><p>The probe can be used to inhibit human phosphomannose isomerase and due to the high homology between other eukaryotic orthologs, it will likely inhibit them as well. The probe can also be used to inhibit this enzyme in living cells since it is membrane permeable. One use of the probe would be to block catabolism of mannose-6-P in cells and direct it toward protein glycosylation. It may have therapeutic potential in phosphomannomutase 2-deficient CDG-Ia patients who are given mannose dietary supplements.</p></div><div id="ml089.s4"><h2 id="_ml089_s4_">1. Scientific Rationale for Project</h2><p>Congenital Disorders of Glycosylation (CDG) are autosomal recessive defects in the synthesis of N-linked oligosaccharide chains (<a class="bk_pop" href="#ml089.r1">1</a>). CDG group I (CDG-I) defects are defined as those caused by mutations in genes encoding enzymes used for the synthesis and transfer of lipid linked oligosaccharide (LLO) to newly synthesized proteins in the lumen of the ER. The steps in this pathway and the genes encoding them are very similar from yeast to human. It requires 30–40 single gene products, each dependent on the previous step in the linear sequence to produce and transfer the LLO to protein. Therefore, mutations in any step may cause a type of CDG. There is considerable overlap in the clinical presentations between different types of CDG and a broad diversity within each type. The most common form of CDG, called Type Ia (CDG-Ia), is caused by defects in PMM2 (Man-6-P to Man-1-P), the gene that encodes phosphomannomutase. Mortality is 20% in the first 5 years, but then patients stabilize. Currently, there is no treatment for the CDG-Ia.</p><p>CDG-Ib patients, who are deficient in phosphomannose isomerase (PMI) catalyzing conversion of Man-6-P to Fru-6-P, are successfully treated with free mannose (<a class="bk_pop" href="#ml089.r2" data-bk-pop-others="ml089.r3 ml089.r4 ml089.r5 ml089.r6">2 – 6</a>). Unfortunately, mannose therapy is not effective for CDG-Ia patients, most likely due to efficient Man-6-P consumption in the PMI reaction (<a class="bk_pop" href="#ml089.r7">7</a>,<a class="bk_pop" href="#ml089.r8">8</a>). It is believed that patients with Congenital Disorder of Glycosylation Type Ia (CDG-Ia) will benefit from dietary mannose if there is a simultaneous reduction of phosphomannose isomerase (PMI) activity. This would allow a modest intracellular accumulation of Man-6-P and drive metabolic flux into the glycosylation pathway using the residual PMM2 activity (<a class="bk_pop" href="#ml089.r9">9</a>). It is assumed that a non-competitive inhibitor would work best in this setting; however, identification of chemical probes with diverse modes of action (MOA) would be advantageous for further characterization of PMI and PMM variants.</p><p>We proposed that CDG-Ia patients will benefit from dietary mannose if we simultaneously reduce PMI activity with a non-competitive or un-competitive inhibitor. This would allow a modest intracellular accumulation of Man-6-P and drive metabolic flux into the glycosylation pathway using the residual PMM2 activity.</p><p>Novel chemical probes elucidated in this way are invaluable tools to help explain the role of PMI in various biochemical pathways, and will ultimately lead to the first therapy for the growing number of CDG-Ia patients.</p></div><div id="ml089.s5"><h2 id="_ml089_s5_">2. Project Description</h2><div id="ml089.s6"><h3>a. The original goal for probe characteristics</h3><p>The original overall goal for this project was to identify novel non-competitive inhibitors of phosphomannose isomerase (PMI) that can be used as a therapeutic for treating patients with Congenital Disorder of Glycosylation Type Ia (CDG-Ia). A non-competitive inhibitor is preferred (yet not required) to avoid competition by the increased Man-6-P level. The main aims undertaken were: 1) Identify small molecule compounds in the MLSMR collection screening 2) Validated the specificity, activity, stability and kinetic behavior of the selected compound(s) 3) Test selected inhibitors of PMI for in cell based assay to determine their effects on glycosylation in intact cells</p></div><div id="ml089.s7"><h3>b. Assay implementation and screening</h3><div id="ml089.s8"><h4>i. PubChem Bioassay Name(s), AID(s), Assay-Type (Primary, DR, Counterscreen, Secondary)</h4><div id="ml089.tu2" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK47345/table/ml089.tu2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml089.tu2_lrgtbl__"><table><thead><tr><th id="hd_h_ml089.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">PubChemBioAssay Name</th><th id="hd_h_ml089.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">AIDs</th><th id="hd_h_ml089.tu2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Probe Type</th><th id="hd_h_ml089.tu2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Assay Type</th><th id="hd_h_ml089.tu2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Assay Format</th><th id="hd_h_ml089.tu2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Assay Detection & well format</th></tr></thead><tbody><tr><td headers="hd_h_ml089.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">HTS identification of compounds inhibiting phosphomannose isomerase (PMI) via a fluorescence intensity assay</td><td headers="hd_h_ml089.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1209" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1209</a></td><td headers="hd_h_ml089.tu2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Inhibitor</td><td headers="hd_h_ml089.tu2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Primary/ Confirmatory</td><td headers="hd_h_ml089.tu2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Biochemical</td><td headers="hd_h_ml089.tu2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Fluorescence 1536 well</td></tr><tr><td headers="hd_h_ml089.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">HTS identification of compounds inhibiting phosphomannose isomerase (PMI) via a fluorescence intensity assay using a high concentration of mannose 6-phosphate [Confirmatory]</td><td headers="hd_h_ml089.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1220" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1220</a></td><td headers="hd_h_ml089.tu2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Inhibitor</td><td headers="hd_h_ml089.tu2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Primary/ Confirmatory/ Mechanistic</td><td headers="hd_h_ml089.tu2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Biochemical</td><td headers="hd_h_ml089.tu2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Fluorescence 1536 well</td></tr><tr><td headers="hd_h_ml089.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Confirmation of compounds inhibiting phosphomannose isomerase (PMI) via a fluorescence intensity assay. [Confirmatory]</td><td headers="hd_h_ml089.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1535" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1535</a></td><td headers="hd_h_ml089.tu2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Inhibitor</td><td headers="hd_h_ml089.tu2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">SAR</td><td headers="hd_h_ml089.tu2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Biochemical</td><td headers="hd_h_ml089.tu2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Fluorescence 384 well</td></tr><tr><td headers="hd_h_ml089.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Confirmation of compounds inhibiting phosphomannose isomerase (PMI) via a fluorescence intensity assay using a high concentration of mannose 6-phosphate. [Confirmatory]</td><td headers="hd_h_ml089.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1536" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1536</a></td><td headers="hd_h_ml089.tu2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Inhibitor</td><td headers="hd_h_ml089.tu2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">SAR/ mechanistic</td><td headers="hd_h_ml089.tu2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Biochemical</td><td headers="hd_h_ml089.tu2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Fluorescence 384 well</td></tr><tr><td headers="hd_h_ml089.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">uHTS Identification of Diaphorase Inhibitors and Chemcical Oxidizers: Counter Screen for Diaphorase-based Primary Assays [Primary Screening]</td><td headers="hd_h_ml089.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1217" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1217</a></td><td headers="hd_h_ml089.tu2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Inhibitor</td><td headers="hd_h_ml089.tu2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Primary/ Counter screen</td><td headers="hd_h_ml089.tu2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Biochemical</td><td headers="hd_h_ml089.tu2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Fluorescence 1536 well</td></tr><tr><td headers="hd_h_ml089.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Counter Screen for Glucose-6-Phosphate Dehydrogenase-based Primary Assay</td><td headers="hd_h_ml089.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1020" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1020</a></td><td headers="hd_h_ml089.tu2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Inhibitor</td><td headers="hd_h_ml089.tu2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Primary/ Counter Screen</td><td headers="hd_h_ml089.tu2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Biochemical</td><td headers="hd_h_ml089.tu2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Fluorescence 1536 well</td></tr><tr><td headers="hd_h_ml089.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Phosophomannose Mutase 2 (PMM2)</td><td headers="hd_h_ml089.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1655" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1655</a></td><td headers="hd_h_ml089.tu2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Inhibitor</td><td headers="hd_h_ml089.tu2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Confirmatory/ Counter screen</td><td headers="hd_h_ml089.tu2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Biochemical</td><td headers="hd_h_ml089.tu2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Fluorescence 1536 well</td></tr><tr><td headers="hd_h_ml089.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">PHOSPHO1</td><td headers="hd_h_ml089.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1666" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1666</a></td><td headers="hd_h_ml089.tu2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Inhibitor</td><td headers="hd_h_ml089.tu2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Secondary DR</td><td headers="hd_h_ml089.tu2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Biochemical</td><td headers="hd_h_ml089.tu2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Fluorescence 384 well</td></tr><tr><td headers="hd_h_ml089.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Screening for Phosphomannose Isomerase inhibitors in cellular based assay using Hela cells.</td><td headers="hd_h_ml089.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1553" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1553</a></td><td headers="hd_h_ml089.tu2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Inhibitor</td><td headers="hd_h_ml089.tu2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Secondary Assay Provider</td><td headers="hd_h_ml089.tu2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Cell-based</td><td headers="hd_h_ml089.tu2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Radioactive water <sup>3</sup>H<sub>2</sub>0 formation</td></tr><tr><td headers="hd_h_ml089.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Toxicity Screening of PMI Inhibitors in Hela cells</td><td headers="hd_h_ml089.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1620" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1620</a></td><td headers="hd_h_ml089.tu2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Inhibitor</td><td headers="hd_h_ml089.tu2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Secondary Assay Provider</td><td headers="hd_h_ml089.tu2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Cell-based</td><td headers="hd_h_ml089.tu2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><sup>35</sup>S protein incorporation</td></tr></tbody></table></div></div></div><div id="ml089.s9"><h4>ii. Assay Rationale & Description</h4><p>The purpose of this assay was to identify inhibitors of human PMI. This was accomplished by using a G6PD- NADPH-coupled assay. In the assay PMI activity was detected through conversion of its product, fructose-6-phosphate, to glucose-6-phosphate catalyzed by phosphoglucose isomerase (PGI) and subsequent oxidation of glucose-6-phosphate to 6-phosphogluconolactone concomitant with NADP-to-NADPH conversion catalyzed by glucose-6-phosphate dehydrogenase (G6PDH). The NADPH was then detected via a resazurin-diaphorase fluorogenic reaction.</p><p>This assay was performed in the presence of near-Km concentrations of the PMI substrate, mannose-6-phosphate, to ensure the identification of inhibitors with diverse Mechanism of Actions (MOAs). Keeping in mind that non- or un-competitive inhibitors might provide a better probe, we also developed and utilized for the full-deck screening the assay performed in the presence of 10xKm of the PMI substrate be better for to help with prioritization of hits for follow-up work. The idea being, that the competitive inhibitors would show much less inhibition in these conditions comparing to the normal screening. Thus, we selected scaffolds that inhibit in both assays with similar potency for further work; the described herein probe originated from this type of scaffold. In addition, we also developed and implemented the following assays for counter screening: G6PDH (primary HTS), diaphorase (primary HTS). Compounds inhibitory in any of these counter-screen assays were excluded from further consideration.</p><div id="ml089.s10"><h5>Protocol</h5><div id="ml089.s11"><h5>PMI assay materials</h5><ol><li class="half_rhythm"><div>Human PMI protein was provided by Dr. Hudson Freeze (Burnham Institute for Medical Research, San Diego, CA). The target protein, recombinant Phosphomannose Isomerase (PMI), was made in 1 L batches from high expressing baculovirus sytems in SF9 insect cells in Dr Hudson Freeze laboratory. .</div></li><li class="half_rhythm"><div>Substrate working solution: 50 mM HEPES, pH 7.4, 0.4 mM Mannose-6- phosphate, 1.6 U/ml Diaphorase, 0.2 mM Resazurin.</div></li><li class="half_rhythm"><div>Enzyme working solution: 50 mM HEPES, pH 7.4, 0.44 mM NADP+, 9.048 mM MgCl2, 0.01% Tween 20, 4.6 ug/ml phosphoglucose isomerase, 30 ng/ml PMI, 1.8 ug/ml G6PDH.</div></li></ol><div id="ml089.tu3" class="table"><h3><span class="title">Table of Reagents and source used in experiments</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK47345/table/ml089.tu3/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml089.tu3_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml089.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">Reagents name</th><th id="hd_h_ml089.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">Vendors name</th></tr></thead><tbody><tr><td headers="hd_h_ml089.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">PhosphoGlucose Isomerase (PGI)</td><td headers="hd_h_ml089.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Roche Diagnostics</td></tr><tr><td headers="hd_h_ml089.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Glucose-6 phosphate Dehydrogenase (G6PD)</td><td headers="hd_h_ml089.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">USB</td></tr><tr><td headers="hd_h_ml089.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Mannose-6 Phosphate</td><td headers="hd_h_ml089.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Sigma-Aldrich</td></tr><tr><td headers="hd_h_ml089.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">NADP</td><td headers="hd_h_ml089.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">ISC/Bioexpress</td></tr><tr><td headers="hd_h_ml089.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Hepes Buffer</td><td headers="hd_h_ml089.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Sigma-Aldrich</td></tr><tr><td headers="hd_h_ml089.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Magnesium Chloride</td><td headers="hd_h_ml089.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Sigma-Aldrich</td></tr></tbody></table></div></div></div><div id="ml089.s12"><h5>PMI HTS protocol</h5><ol><li class="half_rhythm"><div>2 uL of Substrate working solution was added to columns 3–48 of a Costar 1536- well black plate (cat #3724) using a Thermo Multidrop Combi dispenser</div></li><li class="half_rhythm"><div>2 ul of Substrate working solution without mannose-6-p was added to columns 1 and 2 (positive control) of a Costar 1536-well black plate (cat #3724) using a Thermo Multidrop Combi dispenser</div></li><li class="half_rhythm"><div>40 nL of 100% DMSO was added to columns 1–4 using a HighRes biosolutions pintool and V&P Scientific pins</div></li><li class="half_rhythm"><div>40 nL of 2 mM compounds in 100% DMSO were dispensed in columns 5–48 using a HighRes biosolutions pintool and V&P Scientific pins</div></li><li class="half_rhythm"><div>2 uL of Enzyme working solution was added to the whole plate using a Thermo Multidrop Combi dispenser.</div></li><li class="half_rhythm"><div>Plates were incubated at room temperature for 20 min.</div></li><li class="half_rhythm"><div>After 20 minutes the plates were read on a ViewLux plate reader (Perkin Elmer), Ex544, Em590.</div></li><li class="half_rhythm"><div>The screening was performed using a HighRes biosolution fully integrated HTS POD-based system</div></li><li class="half_rhythm"><div>Data analysis was performed using CBIS software (ChemInnovations, Inc).</div></li></ol><p>Compounds showing more than 50% inhibition were requested from MLSMR for dose-response confirmation.</p></div><div id="ml089.s13"><h5>PMI dose-response assay protocol</h5><ol><li class="half_rhythm"><div>9 uL of Substrate working solution was added to columns 3–24 of a Greiner 384-well black plates (cat #784076) using a Thermo Multidrop Combi dispenser</div></li><li class="half_rhythm"><div>9 ul of Substrate working solution without mannose-6-p was added to columns 1 and 2 (positive control) using a Thermo Multidrop Combi dispenser</div></li><li class="half_rhythm"><div>2 uL of serially diluted compounds in 10% DMSO were added to columns 3–22 using Biomek FX</div></li><li class="half_rhythm"><div>2 uL of 10% DMSO were added to columns 1–2, 23–24</div></li><li class="half_rhythm"><div>9 uL of Enzyme working solution was added to the whole plate using a Thermo Multidrop Combi dispenser.</div></li><li class="half_rhythm"><div>Plates were incubated at room temperature for 20 min.</div></li><li class="half_rhythm"><div>After 20 minutes the plates were read on an Analyst plate reader (Molecular Devices), Ex544, Em590.</div></li><li class="half_rhythm"><div>Data analysis was performed using CBIS software (ChemInnovations, Inc).</div></li></ol></div><div id="ml089.s14"><h5>The confirmatory screen</h5><p>The coupled assay is complex and needs to be validated using a simple system. We elected to confirm the results by adding various inhibitors to purified PMI in the presence of [2–3H]Mannose-6-P. The direct action of PMI on this substrate produces <sup>3</sup>H<sub>2</sub>O which can be quantified in a simple “blow-off” (evaporation). This method can be modified for use in cells by providing [2-<sup>3</sup>H-mannose into glycosylation pathway. This assay provides <sup>3</sup>H-mannose to monolayer of human hepatoma cells (C3A) then measures release of <sup>3</sup>H<sub>2</sub>O into growth media by scintillation counting at a fixed time point (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1553" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1553</a>).</p><p>Assay was conducted in 24-well tissue culture plates and Dr. Hudson Freeze laboratory ran the capacity of 6 compounds at 3 concentrations in duplicate (1 plate w/ controls). As additional confirmation, the amount of <sup>3</sup>H-mannose incorporated into cellular protein was measured by TCA precipitation. Successful candidates increased the amount of incorporation into protein and decreased the amount of <sup>3</sup>H<sub>2</sub>O formed.</p></div></div></div><div id="ml089.s15"><h4>iii. Summary of Results</h4><p>194,158 compounds were tested at 20µM and 926 had an activity ≥ 50% in the assay. The average Z′ for the screen was 0.81, signal to background was 3.9, signal to noise was 52.4 and signal window was 19.1. Hits confirmed using DMSO solutions were clustered into 3 series, the benzoisothiazolone series, thiol-triazole series and the dithiazole series. Analog-by-catalog (ABC) SAR studies on <b>the Benzoisothiazolone series</b> are summarized below:</p><p>7 confirmed HTS hits along with 50 analogs were purchased from various vendors for SAR studies. Some SAR can be concluded from this round of study (<a class="figpopup" href="/books/NBK47345/figure/ml089.f1/?report=objectonly" target="object" rid-figpopup="figml089f1" rid-ob="figobml089f1">Figure 1</a>) and some representative examples are shown in <a class="figpopup" href="/books/NBK47345/table/ml089.t1/?report=objectonly" target="object" rid-figpopup="figml089t1" rid-ob="figobml089t1">Table 1</a>.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml089f1" co-legend-rid="figlgndml089f1"><a href="/books/NBK47345/figure/ml089.f1/?report=objectonly" target="object" title="Figure 1" class="img_link icnblk_img figpopup" rid-figpopup="figml089f1" rid-ob="figobml089f1"><img class="small-thumb" src="/books/NBK47345/bin/ml089f1.gif" src-large="/books/NBK47345/bin/ml089f1.jpg" alt="Figure 1" /></a><div class="icnblk_cntnt" id="figlgndml089f1"><h4 id="ml089.f1"><a href="/books/NBK47345/figure/ml089.f1/?report=objectonly" target="object" rid-ob="figobml089f1">Figure 1</a></h4></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml089t1"><a href="/books/NBK47345/table/ml089.t1/?report=objectonly" target="object" title="Table 1" class="img_link icnblk_img figpopup" rid-figpopup="figml089t1" rid-ob="figobml089t1"><img class="small-thumb" src="/books/NBK47345/table/ml089.t1/?report=thumb" src-large="/books/NBK47345/table/ml089.t1/?report=previmg" alt="Table 1. SAR Studies." /></a><div class="icnblk_cntnt"><h4 id="ml089.t1"><a href="/books/NBK47345/table/ml089.t1/?report=objectonly" target="object" rid-ob="figobml089t1">Table 1</a></h4><p class="float-caption no_bottom_margin">SAR Studies. </p></div></div></div></div><div id="ml089.s16"><h3>c. Probe Optimization</h3><div id="ml089.s17"><h4>i. SAR & chemistry strategy (including structure and data) that led to the probe</h4><div id="ml089.f2" class="figure bk_fig"><div class="graphic"><img src="/books/NBK47345/bin/ml089f2.jpg" alt="Figure 2. SAR strategy for CID-22416235." /></div><h3><span class="label">Figure 2</span><span class="title">SAR strategy for CID-22416235</span></h3></div><p>The SAR around CID-22416235 is illustrated in <a class="figpopup" href="/books/NBK47345/figure/ml089.f1/?report=objectonly" target="object" rid-figpopup="figml089f1" rid-ob="figobml089f1">Figure 1</a>. Three key structural features amenable to chemical derivatization were recognized to be responsible for biological activity: (a) the benzoisothiazolone fused aryl ring substituents, (b) the benzoisothiazolone ring heteroatoms, and (c) the aryl substituents. The overall goals of the SAR optimization efforts were two-fold: (<a class="bk_pop" href="#ml089.r1">1</a>) produce inhibitors showing increased potency <i>in vitro</i> against the PMI enzyme that show minimal activity against PMM and (<a class="bk_pop" href="#ml089.r2">2</a>) demonstrate cell-based efficacy and reduced cellular toxicity of these analogues. Cell based efficacy was determined at 3 concentrations, and the compounds which were toxic showed decreasing activity as concentration was increased. The <i>in vitro</i> enzyme inhibition and cell-based efficacy data for selected analogues of CID-22416235 are shown in <a class="figpopup" href="/books/NBK47345/table/ml089.t2/?report=objectonly" target="object" rid-figpopup="figml089t2" rid-ob="figobml089t2">Table 2</a>. Compound CID-1510389 (MLS-0315771) was the primary lead compound based on the initial <i>in vitro</i> HTS data. While this compound was active in both the <i>in vitro</i> enzyme assay and the cell-based assay, it showed significant cellular toxicity, as can be seen with the dramatic reduction in cellular efficacy as concentration was increased. Thus, a variety of analogues were prepared to both reduce toxicity of these analogues and elucidate the key features of CID-1510389 (MLS-0315771) that were responsible for its activity. As can be seen in <a class="figpopup" href="/books/NBK47345/table/ml089.t1/?report=objectonly" target="object" rid-figpopup="figml089t1" rid-ob="figobml089t1">Table 1</a>, removal of either nitrogen or sulfur from the benzoisothiazolone core completely abolishes both PMI and cellular activity [CID-4617895 (MLS-0390881) and CID-25067464 (MLS-0315862) respectively]. Also, replacing the sulfur with another heteroatom, e.g. nitrogen as in CID-13947703 (MLS-0315920), also furnishes analogues without detectable activity. This demonstrated the importance of both the nitrogen and sulfur atoms in the core. The initial lead (CID-1510389 (MLS-0315771)) had a fluorine atom in the 4 position. Additional substitution patterns were synthesized with the goal of lessening cellular toxicity. When the fluorine substituent was moved to the 5 position, as seen in CID-25181201 (MLS-0315923), a lessening of the toxicity was seen as indicated by more activity being retained at 50 µM as compared to the 4-F analogue. It was evident from the observation that the 25 µM dose had more activity than the 50 µM dose, there was still appreciable toxicity. However, the 5-fluoro analogues indeed furnish potent compounds with reduced cellular toxicity. Additional compounds with 5-F substitution patterns showed dose dependent increases in activity, indicative of less toxicity, such as CID-25181243 (MLS-0390936). Finally, optimization of the aromatic portion of the molecule was conducted on both the 5-F and unsubstituted benzoisothiazolone. It was found that para and bis-ortho, meta substituted analogues achieved potency requirements in the enzyme assay. However, dramatic differences were seen in cellular toxicity amongst these. After judicious exploration of aryl substituents, two compounds showed promising <i>in vitro</i> inhibition as well as dose-dependent cellular efficacy with minimal indications of toxicity (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1620" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1620</a>), CID-22416276 (MLS-0390876) and CID-25181243. In fact, these compounds had almost identical activity profiles. However, when tested in the counter assay against the PMM enzyme, CID-22416276 (MLS-0390876) had an IC<sub>50</sub> of 22.3 µM while the probe compound CID-25181243 was completely inactive when tested at concentrations up to 100 µM. Thus, CID-22416235 had the most favorable profile of enzyme activity and selectivity, cellular efficacy, and minimum toxicity.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml089t2"><a href="/books/NBK47345/table/ml089.t2/?report=objectonly" target="object" title="Table 2" class="img_link icnblk_img figpopup" rid-figpopup="figml089t2" rid-ob="figobml089t2"><img class="small-thumb" src="/books/NBK47345/table/ml089.t2/?report=thumb" src-large="/books/NBK47345/table/ml089.t2/?report=previmg" alt="Table 2. In vitro enzyme activity and cellular efficacy data." /></a><div class="icnblk_cntnt"><h4 id="ml089.t2"><a href="/books/NBK47345/table/ml089.t2/?report=objectonly" target="object" rid-ob="figobml089t2">Table 2</a></h4><p class="float-caption no_bottom_margin"><i>In vitro</i> enzyme activity and cellular efficacy data. Cellular data is presented at 3 concentrations. Decreasing cell efficacy with increasing concentration is indicative of cellular toxicity. </p></div></div></div></div></div><div id="ml089.s18"><h2 id="_ml089_s18_">3. Probe</h2><div id="ml089.s20"><h3>a. Chemical name</h3><p>5-fluoro-2-phenyl-1,2-benzothiazol-3-one <b>[<a href="/pcsubstance/?term=ML089[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML089</a>]</b></p></div><div id="ml089.s21"><h3>b. Probe chemical structure</h3><div id="ml089.fu2" class="figure"><div class="graphic"><img src="/books/NBK47345/bin/ml089fu1.jpg" alt="Image ml089fu1" /></div></div></div><div id="ml089.s22"><h3>c. Structural Verification Information of probe SID</h3><p><a href="https://pubchem.ncbi.nlm.nih.gov/substance/57287553" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-57287553</a>.</p><div id="ml089.fu3" class="figure"><div class="graphic"><img src="/books/NBK47345/bin/ml089fu22.jpg" alt="Image ml089fu22" /></div></div><div id="ml089.fu4" class="figure"><div class="graphic"><img src="/books/NBK47345/bin/ml089fu23.jpg" alt="Image ml089fu23" /></div></div></div><div id="ml089.s23"><h3>d. PubChem CID (corresponding to the SID)</h3><p>CID-22416235</p></div><div id="ml089.s24"><h3>e. Availabilty from a vendor</h3><p>This probe is not commercially available from vendors.</p></div><div id="ml089.s25"><h3>f. MLS#'s of probe molecule and five related samples that were submitted to the SMR collection</h3><div id="ml089.tu4" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK47345/table/ml089.tu4/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml089.tu4_lrgtbl__"><table><thead><tr><th id="hd_h_ml089.tu4_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Probe /Analog</th><th id="hd_h_ml089.tu4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">MLS-# (BCCG#)</th><th id="hd_h_ml089.tu4_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CID</th><th id="hd_h_ml089.tu4_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">SID</th><th id="hd_h_ml089.tu4_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Source (vendor or BCCG syn)</th><th id="hd_h_ml089.tu4_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Amt (mg)</th><th id="hd_h_ml089.tu4_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Date ordered/ submitted</th></tr></thead><tbody><tr><td headers="hd_h_ml089.tu4_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Probe</td><td headers="hd_h_ml089.tu4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0315921</td><td headers="hd_h_ml089.tu4_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">22416235</td><td headers="hd_h_ml089.tu4_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/57287553" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">57287553</a></td><td headers="hd_h_ml089.tu4_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">BCCG syn</td><td headers="hd_h_ml089.tu4_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">20</td><td headers="hd_h_ml089.tu4_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">4/15/09</td></tr><tr><td headers="hd_h_ml089.tu4_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Analog 1</td><td headers="hd_h_ml089.tu4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0315923</td><td headers="hd_h_ml089.tu4_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">25181201</td><td headers="hd_h_ml089.tu4_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/57287555" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">57287555</a></td><td headers="hd_h_ml089.tu4_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">BCCG syn</td><td headers="hd_h_ml089.tu4_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">20</td><td headers="hd_h_ml089.tu4_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">4/15/09</td></tr><tr><td headers="hd_h_ml089.tu4_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Analog 2</td><td headers="hd_h_ml089.tu4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0390936</td><td headers="hd_h_ml089.tu4_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">25181243</td><td headers="hd_h_ml089.tu4_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/57287680" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">57287680</a></td><td headers="hd_h_ml089.tu4_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">BCCG syn</td><td headers="hd_h_ml089.tu4_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">20</td><td headers="hd_h_ml089.tu4_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">4/15/09</td></tr><tr><td headers="hd_h_ml089.tu4_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Analog 3</td><td headers="hd_h_ml089.tu4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0390876</td><td headers="hd_h_ml089.tu4_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">22416276</td><td headers="hd_h_ml089.tu4_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/57287618" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">57287618</a></td><td headers="hd_h_ml089.tu4_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">BCCG syn</td><td headers="hd_h_ml089.tu4_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">20</td><td headers="hd_h_ml089.tu4_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">4/15/09</td></tr><tr><td headers="hd_h_ml089.tu4_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Analog 4</td><td headers="hd_h_ml089.tu4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0390935</td><td headers="hd_h_ml089.tu4_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">25181242</td><td headers="hd_h_ml089.tu4_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/57287679" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">57287679</a></td><td headers="hd_h_ml089.tu4_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">BCCG syn</td><td headers="hd_h_ml089.tu4_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">20</td><td headers="hd_h_ml089.tu4_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">4/15/09</td></tr><tr><td headers="hd_h_ml089.tu4_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Analog 5</td><td headers="hd_h_ml089.tu4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0315771</td><td headers="hd_h_ml089.tu4_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1510389</td><td headers="hd_h_ml089.tu4_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/56373807" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">56373807</a></td><td headers="hd_h_ml089.tu4_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Chem Block</td><td headers="hd_h_ml089.tu4_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">20</td><td headers="hd_h_ml089.tu4_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">4/15/09</td></tr></tbody></table></div></div></div><div id="ml089.s26"><h3>g. Mode of action for biological activity of probe</h3><p>The mode of action is not yet fully characterized. The whole benzoisothiazolone scaffold with all its primary hits was identified as non- or un-competitive since it inhibited irrespective of substrate concentration. As alterations to the structure of the primary hits that were made to arrive at the probe are limited, the probe is very likely to have the same MOA.</p></div><div id="ml089.s27"><h3>h. Detailed synthetic pathway for making probe</h3><div id="ml089.f3" class="figure bk_fig"><div class="graphic"><img src="/books/NBK47345/bin/ml089f3.jpg" alt="Scheme 1. Synthesis of CID-22416235. aphenyliodine(III) bis(trifluoroacetate)." /></div><h3><span class="label">Scheme 1</span><span class="title">Synthesis of CID-22416235. <sup>a</sup>phenyliodine(III) bis(trifluoroacetate)</span></h3></div></div><div id="ml089.s28"><h3>i. Summary of probe properties (solubility, absorbance/fluorescence, reactivity, toxicity, etc.)</h3><p>CID-22416235 demonstrated potent inhibition and also demonstrated selectivity within the class.</p></div><div id="ml089.s29"><h3>j. Properties Computed from Structure</h3><div id="ml089.tu5" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK47345/table/ml089.tu5/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml089.tu5_lrgtbl__"><table><thead><tr><th id="hd_h_ml089.tu5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Molecular Property</th><th id="hd_h_ml089.tu5_1_1_1_2" rowspan="1" colspan="1" style="text-align:right;vertical-align:bottom;">Value</th></tr></thead><tbody><tr><td headers="hd_h_ml089.tu5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Molecular Weight</td><td headers="hd_h_ml089.tu5_1_1_1_2" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">245.27212</td></tr><tr><td headers="hd_h_ml089.tu5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Molecular Formula</td><td headers="hd_h_ml089.tu5_1_1_1_2" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">C<sub>13</sub>H<sub>8</sub>FNOS</td></tr><tr><td headers="hd_h_ml089.tu5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">XLogP3-AA</td><td headers="hd_h_ml089.tu5_1_1_1_2" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">3.1</td></tr><tr><td headers="hd_h_ml089.tu5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H-Bond Donor</td><td headers="hd_h_ml089.tu5_1_1_1_2" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml089.tu5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H-Bond Acceptor</td><td headers="hd_h_ml089.tu5_1_1_1_2" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">2</td></tr><tr><td headers="hd_h_ml089.tu5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Rotatable Bond Count</td><td headers="hd_h_ml089.tu5_1_1_1_2" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">1</td></tr><tr><td headers="hd_h_ml089.tu5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Exact Mass</td><td headers="hd_h_ml089.tu5_1_1_1_2" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">245.031063</td></tr><tr><td headers="hd_h_ml089.tu5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MonoIsotopic Mass</td><td headers="hd_h_ml089.tu5_1_1_1_2" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">245.031063</td></tr><tr><td headers="hd_h_ml089.tu5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Topological Polar Surface Area</td><td headers="hd_h_ml089.tu5_1_1_1_2" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">45.6</td></tr><tr><td headers="hd_h_ml089.tu5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Heavy Atom Count</td><td headers="hd_h_ml089.tu5_1_1_1_2" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">17</td></tr><tr><td headers="hd_h_ml089.tu5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Formal Charge</td><td headers="hd_h_ml089.tu5_1_1_1_2" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml089.tu5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Complexity</td><td headers="hd_h_ml089.tu5_1_1_1_2" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">306</td></tr><tr><td headers="hd_h_ml089.tu5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Isotope Atom Count</td><td headers="hd_h_ml089.tu5_1_1_1_2" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml089.tu5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Defined Atom StereoCenter Count</td><td headers="hd_h_ml089.tu5_1_1_1_2" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml089.tu5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Undefined Atom StereoCenter Count</td><td headers="hd_h_ml089.tu5_1_1_1_2" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml089.tu5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Defined Bond StereoCenter Count</td><td headers="hd_h_ml089.tu5_1_1_1_2" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml089.tu5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Undefined Bond StereoCenter Count</td><td headers="hd_h_ml089.tu5_1_1_1_2" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml089.tu5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Covalently-Bonded Unit Count</td><td headers="hd_h_ml089.tu5_1_1_1_2" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">1</td></tr></tbody></table></div></div></div></div><div id="ml089.s30"><h2 id="_ml089_s30_">4. Appendices</h2><div id="ml089.s32"><h3>a. Comparative data on (1) probe, (2) similar compound structures (establishing SAR) and (3) prior probes</h3><p>See list of compounds ordered for SAR by catalog as attached to end of this probe report.</p></div><div id="ml089.s33"><h3>b. Comparative data showing probe specificity for target</h3><p>See Table 3 above for selectivity</p></div></div><div id="ml089.s34"><h2 id="_ml089_s34_">5. Bibliography</h2><dl class="temp-labeled-list"><dt>1.</dt><dd><div class="bk_ref" id="ml089.r1">Freeze HH. Genetic defects in the human glycome. <span><span class="ref-journal">Nat Rev Genet. </span>2006;<span class="ref-vol">7</span>:537–551.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16755287" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16755287</span></a>]</div></dd><dt>2.</dt><dd><div class="bk_ref" id="ml089.r2">Alper J. Searching for medicine’s sweet spot. <span><span class="ref-journal">Science. </span>2001;<span class="ref-vol">291</span>:2338–2343.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11269308" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11269308</span></a>]</div></dd><dt>3.</dt><dd><div class="bk_ref" id="ml089.r3">Niehues R, Hasilik M, Alton G, Körner C, Schiebe-Sukumar M, Koch HG, Zimmer KP, Wu R, Harms E, Reiter K, von Figura K, Freeze HH, Harms HK, Marquardt T. Carbohydratedeficient glycoprotein syndrome type Ib. Phosphomannose isomerase deficiency and mannose therapy. <span><span class="ref-journal">J Clin Invest. </span>1998;<span class="ref-vol">101</span>:1414–1420.</span> [<a href="/pmc/articles/PMC508719/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC508719</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/9525984" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9525984</span></a>]</div></dd><dt>4.</dt><dd><div class="bk_ref" id="ml089.r4">Babovic-Vuksanovic D, Patterson MC, Schwenk WF, O’Brien JF, Vockley J, Freeze HH, Mehta DP, Michels VV. Severe hypoglycemia as a presenting symptom of carbohydrate deficient glycoprotein syndrome. <span><span class="ref-journal">J Pediatr. </span>1999;<span class="ref-vol">135</span>:775–781.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/10586187" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10586187</span></a>]</div></dd><dt>5.</dt><dd><div class="bk_ref" id="ml089.r5">de Lonlay P, Cuer M, Vuillaumier-Barrot S, Beaune G, Castelnau P, Kretz M, Durand G, Saudubray JM, Seta N. Hyperinsulinemic hypoglycemia as a presenting sign in phosphomannose isomerase deficiency: A new manifestation of carbohydrate-deficient glycoprotein syndrome treatable with mannose. <span><span class="ref-journal">J Pediatr. </span>1999;<span class="ref-vol">135</span>:379–383.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/10484808" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10484808</span></a>]</div></dd><dt>6.</dt><dd><div class="bk_ref" id="ml089.r6">Westphal V, Kjaergaard S, Davis JA, Peterson SM, Skovby F, Freeze HH. Genetic and metabolic analysis of the first adult with congenital disorder of glycosylation type ib: long-term outcome and effects of mannose supplementation. <span><span class="ref-journal">Mol Genet Metab. </span>2001;<span class="ref-vol">73</span>:77–85.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11350186" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11350186</span></a>]</div></dd><dt>7.</dt><dd><div class="bk_ref" id="ml089.r7">Rush JS, Panneerselvam K, Waechter CJ, Freeze HH. Mannose supplementation corrects GDP-mannose deficiency in cultured fibroblasts from some patients with Congenital Disorders of Glycosylation (CDG). <span><span class="ref-journal">Glycobiology. </span>2000;<span class="ref-vol">10</span>:829–835.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/10929009" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10929009</span></a>]</div></dd><dt>8.</dt><dd><div class="bk_ref" id="ml089.r8">Panneerselvam K, Freeze HH. Mannose corrects altered N-glycosylation in carbohydratedeficient glycoprotein syndrome fibroblasts. <span><span class="ref-journal">J Clin Invest. </span>1996;<span class="ref-vol">97</span>:1478–1487.</span> [<a href="/pmc/articles/PMC507208/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC507208</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/8617881" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8617881</span></a>]</div></dd><dt>9.</dt><dd><div class="bk_ref" id="ml089.r9">Freeze HH. Chapter 6: Monosaccharide Metabolism. In: Varki A, Cummings R, Esko JD, Freeze HH, Hart G, Marth JD, editors. <span class="ref-journal">Essentials of Glycobiology.</span> New York: Cold Spring Harbor Laboratory Press; 1999. pp. 69–84.</div></dd></dl></div><div id="bk_toc_contnr"></div></div></div>
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<div xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Views</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="PDF_download" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="/books/NBK47345/?report=reader">PubReader</a></li><li><a href="/books/NBK47345/?report=printable">Print View</a></li><li><a data-jig="ncbidialog" href="#_ncbi_dlg_citbx_NBK47345" data-jigconfig="width:400,modal:true">Cite this Page</a><div id="_ncbi_dlg_citbx_NBK47345" style="display:none" title="Cite this Page"><div class="bk_tt">Hedrick M, Brown B, Rascon J, et al. Therapeutic Inhibitors of Phosphomannose Isomerase - Probe 1. 2009 Apr 21 [Updated 2010 Sep 2]. In: Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010-. <span class="bk_cite_avail"></span></div></div></li><li><a href="/books/NBK47345/pdf/Bookshelf_NBK47345.pdf">PDF version of this page</a> (363K)</li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>In this Page</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="page-toc" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="#ml089.s2" ref="log$=inpage&link_id=inpage">Probe Structure & Characteristics</a></li><li><a href="#ml089.s3" ref="log$=inpage&link_id=inpage">Recommendations for the scientific use of this probe</a></li><li><a href="#ml089.s4" ref="log$=inpage&link_id=inpage">Scientific Rationale for Project</a></li><li><a href="#ml089.s5" ref="log$=inpage&link_id=inpage">Project Description</a></li><li><a href="#ml089.s18" ref="log$=inpage&link_id=inpage">Probe</a></li><li><a href="#ml089.s30" ref="log$=inpage&link_id=inpage">Appendices</a></li><li><a href="#ml089.s34" ref="log$=inpage&link_id=inpage">Bibliography</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Related information</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="discovery_db_links" id="Shutter"></a></div><div class="portlet_content"><ul><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pmc&DbFrom=books&Cmd=Link&LinkName=books_pmc_refs&IdsFromResult=2359032" ref="log$=recordlinks">PMC</a><div class="brieflinkpop offscreen_noflow">PubMed Central citations</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pcassay&DbFrom=books&Cmd=Link&LinkName=books_pcassay_probe&IdsFromResult=2359032" ref="log$=recordlinks">PubChem BioAssay for Chemical Probe</a><div class="brieflinkpop offscreen_noflow">PubChem BioAssay records reporting screening data for the development of the chemical probe(s) described in this book chapter</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pcsubstance&DbFrom=books&Cmd=Link&LinkName=books_pcsubstance&IdsFromResult=2359032" ref="log$=recordlinks">PubChem Substance</a><div class="brieflinkpop offscreen_noflow">Related PubChem Substances</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pubmed&DbFrom=books&Cmd=Link&LinkName=books_pubmed_refs&IdsFromResult=2359032" ref="log$=recordlinks">PubMed</a><div class="brieflinkpop offscreen_noflow">Links to PubMed</div></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Similar articles in PubMed</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="PBooksDiscovery_RA" id="Shutter"></a></div><div class="portlet_content"><ul><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/21433366" ref="ordinalpos=1&linkpos=1&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Therapeutic Inhibitors of Phosphomannose Isomerase - 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