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<script type="text/javascript" src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.boots.min.js"> </script><title>An inhibitor of the Cdc2-like kinase 4 (Clk4) - 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="An inhibitor of the Cdc2-like kinase 4 (Clk4)">
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<meta name="citation_publisher" content="National Center for Biotechnology Information (US)">
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<meta name="citation_date" content="2011/03/03">
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<meta name="citation_author" content="Andrew S Rosenthal">
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<meta name="citation_author" content="Cordelle Tanega">
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<meta name="citation_author" content="Min Shen">
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<meta name="citation_author" content="Bryan T Mott">
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<meta name="citation_author" content="James M Bougie">
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<meta name="citation_author" content="Dac-Trung Nguyen">
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<meta name="citation_author" content="Tom Misteli">
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<meta name="citation_author" content="Douglas S Auld">
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<meta name="citation_author" content="David J Maloney">
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<meta name="citation_author" content="Craig J Thomas">
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<meta name="DC.Title" content="An inhibitor of the Cdc2-like kinase 4 (Clk4)">
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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="Andrew S Rosenthal">
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<meta name="DC.Contributor" content="Cordelle Tanega">
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<meta name="DC.Contributor" content="Min Shen">
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<meta name="DC.Contributor" content="Bryan T Mott">
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<meta name="DC.Contributor" content="James M Bougie">
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<meta name="DC.Contributor" content="Dac-Trung Nguyen">
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<meta name="DC.Contributor" content="Tom Misteli">
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<meta name="DC.Contributor" content="Douglas S Auld">
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<meta name="DC.Contributor" content="David J Maloney">
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<meta name="DC.Contributor" content="Craig J Thomas">
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<meta name="DC.Date" content="2011/03/03">
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<meta name="description" content="The Cdc2-like kinases (Clk’s) and the dual-specificity tyrosine phosphorylation-regulated kinases (Dyrk’s) have specified roles in gene splicing. Specifically, the Clk class of enzymes has been shown to phosphorylate the serine- and arginine-rich (SR) proteins, which are a major component of the spliceosome. Dyrk1A has been shown to accumulate in nuclear speckles, where it interacts and activates splicing factors. It has been hypothesized that inhibition of these targets may offer a mechanism to control splicing. This probe represents our continued examination of substituted 6-arylquinazolin-4-amines as Clk/Dyrk inhibitors. Several of the most potent inhibitors, including ML167 (CID 44968231) were validated as being highly selective within a comprehensive kinome scan. Appropriate aqueous solubility and stability were found for this agent.">
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<meta name="og:description" content="The Cdc2-like kinases (Clk’s) and the dual-specificity tyrosine phosphorylation-regulated kinases (Dyrk’s) have specified roles in gene splicing. Specifically, the Clk class of enzymes has been shown to phosphorylate the serine- and arginine-rich (SR) proteins, which are a major component of the spliceosome. Dyrk1A has been shown to accumulate in nuclear speckles, where it interacts and activates splicing factors. It has been hypothesized that inhibition of these targets may offer a mechanism to control splicing. This probe represents our continued examination of substituted 6-arylquinazolin-4-amines as Clk/Dyrk inhibitors. Several of the most potent inhibitors, including ML167 (CID 44968231) were validated as being highly selective within a comprehensive kinome scan. Appropriate aqueous solubility and stability were found for this agent.">
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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="_NBK56236_"><span class="title" itemprop="name">An inhibitor of the Cdc2-like kinase 4 (Clk4)</span></h1><p class="contribs">Rosenthal AS, Tanega C, Shen M, et al.</p><p class="fm-aai"><a href="#_NBK56236_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 Cdc2-like kinases (Clk’s) and the dual-specificity tyrosine phosphorylation-regulated kinases (Dyrk’s) have specified roles in gene splicing. Specifically, the Clk class of enzymes has been shown to phosphorylate the serine- and arginine-rich (SR) proteins, which are a major component of the spliceosome. Dyrk1A has been shown to accumulate in nuclear speckles, where it interacts and activates splicing factors. It has been hypothesized that inhibition of these targets may offer a mechanism to control splicing. This probe represents our continued examination of substituted 6-arylquinazolin-4-amines as Clk/Dyrk inhibitors. Several of the most potent inhibitors, including <a href="/pcsubstance/?term=ML167[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML167</a> (CID 44968231) were validated as being highly selective within a comprehensive kinome scan. Appropriate aqueous solubility and stability were found for this agent.</p></div><div class="h2"></div><p><b>Assigned Assay Grant #:</b> R03 MH084827</p><p><b>Screening Center Name & PI:</b> NIH Chemical Genomics Center & Dr. Christopher P. Austin</p><p><b>Chemistry Center Name & PI:</b> NIH Chemical Genomics Center & Dr. Christopher P. Austin</p><p><b>Assay Submitter & Institution:</b> Dr. Tom Misteli, NCI, NIH</p><p><b>PubChem Summary Bioassay Identifier (AID):</b>
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<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1997" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1997</a></p><div id="ml167.s1"><h2 id="_ml167_s1_">Probe Structure & Characteristics</h2><div id="ml167.fu1" class="figure bk_fig"><div class="graphic"><img src="/books/NBK56236/bin/ml167fu1.jpg" alt="ML167." /></div><h3><span class="title"><a href="/pcsubstance/?term=ML167[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML167</a></span></h3></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml167tu1"><a href="/books/NBK56236/table/ml167.tu1/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figml167tu1" rid-ob="figobml167tu1"><img class="small-thumb" src="/books/NBK56236/table/ml167.tu1/?report=thumb" src-large="/books/NBK56236/table/ml167.tu1/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ml167.tu1"><a href="/books/NBK56236/table/ml167.tu1/?report=objectonly" target="object" rid-ob="figobml167tu1">Table</a></h4></div></div></div><div id="ml167.s2"><h2 id="_ml167_s2_">Recommendations for scientific use of the probe</h2><p>Kinases are a major target for pharmacological intervention, and kinase inhibitors (both specific and promiscuous) represent important probes and drugs. Small molecule probes that target specific kinases represent critical tools for exploring and controlling cell function. The Cdc2-like kinases (Clk’s) and the dual-specificity tyrosine phosphorylation-regulated kinases (Dyrk’s) are two classes of enzymes that have been shown to phosphorylate specific proteins within the spliceosome; therefore, they are considered important targets for the modulation of gene splicing events. In addition to the agents reported in these reports, there is only one other reported Clk4 inhibitor, which was found to be somewhat promiscuous versus a kinase panel. Small molecule inhibitors of all 4 isoforms of the Clk family and both the Dyrk1A and Dyrk1B family, with varying selectivity profiles, will be of great utility to the study of these kinases as modulators of gene splicing, as well as other cellular events. The probe described here represents the first fully selective inhibitor of Cdc2-like kinase 4 (Clk4). This probe compound will be useful for the scientific community in unraveling the phenotype associated solely with Clk4 down-regulation without complication arising from the inhibition of related kinases. Particularly, given the reported role of the Clk family as a specific modulator of SR proteins, this probe will be useful in exploring the specific functions of Clk4 in terms of gene splicing.</p><div id="ml167.fu2" class="figure"><div class="graphic"><img src="/books/NBK56236/bin/ml167fu2.jpg" alt="Image ml167fu2" /></div></div></div><div id="ml167.s3"><h2 id="_ml167_s3_">1. Introduction</h2><p>The removal of intron sequences from genes occurs via the actions of the spliceosome, a protein complex that removes intervening sequences at the nuclear pre-mRNA level to afford properly coded mRNA for translation<a class="bibr" href="#ml167.r1" rid="ml167.r1">1</a>,<a class="bibr" href="#ml167.r2" rid="ml167.r2">2</a>. Many genes produce multiple mRNA isoforms through the actions of alternative splicing and importantly, numerous human diseases are caused by improper splicing<a class="bibr" href="#ml167.r3" rid="ml167.r3">3</a>. Exogenous manipulation of the spliceosome is theorized to be a powerful means to controlling gene translation and ultimately correct disease phenotypes via rectification of splicing abnormalities. There are several reports of kinases that alter the function of the spliceosome. Among these are the Cdc2-like kinase (Clk) family<a class="bibr" href="#ml167.r4" rid="ml167.r4">4</a>. A major target of Clk kinases is the prominent family of serine- and arginine-rich (SR) splicing proteins<a class="bibr" href="#ml167.r5" rid="ml167.r5">5</a>,<a class="bibr" href="#ml167.r6" rid="ml167.r6">6</a>, which are involved in the assembly of the spliceosome and are implicated in both constitutive and alternative splicing control and selection of splicing sites<a class="bibr" href="#ml167.r7" rid="ml167.r7">7</a>,<a class="bibr" href="#ml167.r8" rid="ml167.r8">8</a>. The Clk family contains four characterized isoforms (Clk1, Clk2, Clk3 and Clk4). The Clks are capable of auto-phosphorylation (at serine, threonine and tyrosine residues) and phosphorylation of exogenous proteins (at serine and threonine residues). Members of the Clk family have been implicated in the regulation of alternative splicing of PKCβII, TF, Tau and β-globin pre-mRNA. These studies suggest that small molecule modulation of the Clk family of kinases may represent an important mechanism for the control of mRNA splicing.</p><p>Hagiwara and coworkers have reported TG003 (<b>1</b>) (<a class="figpopup" href="/books/NBK56236/figure/ml167.f1/?report=objectonly" target="object" rid-figpopup="figml167f1" rid-ob="figobml167f1">Figure 1</a>) as a small molecule with low-nanomolar IC<sub>50</sub> values versus Clk1 and Clk4<a class="bibr" href="#ml167.r9" rid="ml167.r9">9</a>. The report does not define the selectivity of TG003 beyond the Clk family and 4 additional kinases (PKA, PKC, SRPK1 and SRPK2). We have recently reported on NCGC00010037 (CID 3232621; <a href="https://pubchem.ncbi.nlm.nih.gov/substance/85239684" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 85239684</a>) (<b>2</b>), a quinazoline-based ATP-competitive inhibitor of the Clk1, Clk4 and Dyrk1A that retains good potency and selectivity across a panel of 402 kinases (<a class="figpopup" href="/books/NBK56236/figure/ml167.f1/?report=objectonly" target="object" rid-figpopup="figml167f1" rid-ob="figobml167f1">Figure 1</a>). Mott <i>et al</i> recently detailed the selectivity of TG003 versus the same 402 kinase panel and revealed that TG003 had several activities, including 19nM, 95nM and 30nM versus Clk1, Clk2 and Clk4, respectively with several additional activities (CSNK1D (150nM), CSNK1E (300nM), Dyrk1A (12nM), Dyrk1B (130nM), PIM1 (130nM), PIM3 (280nM) and Ysk4 (290nM))<a class="bibr" href="#ml167.r10" rid="ml167.r10">10</a>. The patent literature revealed structurally similar benzothiazole <b>1a</b> from Sirtris Pharmaceuticals<a class="bibr" href="#ml167.r11" rid="ml167.r11">11</a> and a substituted quinoline from Chronogen, Inc.<a class="bibr" href="#ml167.r12" rid="ml167.r12">12</a> reported to have activity versus Clk1 (<a class="figpopup" href="/books/NBK56236/figure/ml167.f1/?report=objectonly" target="object" rid-figpopup="figml167f1" rid-ob="figobml167f1">Figure 1</a>). Indole <b>KH-CB19</b> was recently revealed as a potent (20nM) ATP competitive Clk1 inhibitor with good selectivity over Clk3 via a unique binding mode<a class="bibr" href="#ml167.r13" rid="ml167.r13">13</a>.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml167f1" co-legend-rid="figlgndml167f1"><a href="/books/NBK56236/figure/ml167.f1/?report=objectonly" target="object" title="Figure 1" class="img_link icnblk_img figpopup" rid-figpopup="figml167f1" rid-ob="figobml167f1"><img class="small-thumb" src="/books/NBK56236/bin/ml167f1.gif" src-large="/books/NBK56236/bin/ml167f1.jpg" alt="Figure 1. Dendrogram representation of the selectivity profile for kinase binding by TG003 (1) and 2 within a panel of 402 kinases." /></a><div class="icnblk_cntnt" id="figlgndml167f1"><h4 id="ml167.f1"><a href="/books/NBK56236/figure/ml167.f1/?report=objectonly" target="object" rid-ob="figobml167f1">Figure 1</a></h4><p class="float-caption no_bottom_margin">Dendrogram representation of the selectivity profile for kinase binding by TG003 (<i>1</i>) and <i>2</i> within a panel of 402 kinases. </p></div></div><div id="ml167.fu3" class="figure"><div class="graphic"><img src="/books/NBK56236/bin/ml167fu3.jpg" alt="Image ml167fu3" /></div></div><p>Based upon the potency and selectivity for <b>2,</b> we next aimed to understand the binding mechanism of this chemotype at Clk1 and Clk4. We explored the binding modality by examining the inhibitory capacity of <b>2</b> in settings that varied both compound and substrate concentrations. The dose response curve of <b>2</b> in the presence of three different ATP concentrations demonstrated a loss in potency when ATP levels rose. Conversely, the % activity of <b>1</b> in the presence of varying concentrations of the peptide substrate had no affect on the compound potency. This data strongly suggests that this agent is an ATP-competitive inhibitor of Clk1 and Clk4.</p><p>Activity for <b>1</b>: Clk1 = 19nM, Clk2 = 95nM, Clk3 = 3000nM, Clk4 = 30nM, CSNK1D = 150nM, CSNK1E = 300nM, CSNK1G2 = 270nM, CSNK1G3 = 290nM, Dyrk1A = 12nM, Dyrk1B = 130nM, PIM1 = 130nM, PIM3 = 280nM, Ysk4 = 290nM.</p><p>Activity for <b>2</b>: Clk1 = 37nM, Clk2 = 680nM, Clk3 = 470nM, Clk4 = 50nM, Dyrk1A = 27nM, Dyrk1B = 430nM, EGFR = 230nM.</p><p><i>Note:</i>
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<b><i>2</i></b>
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<i>was active (>250nM) versus numerous EGFR mutants.</i></p><p>The ability to ascribe a phenotype to the specific, pharmacological down-regulation of a target is a key aspect of understanding the role of various cellular targets within cellular pathways and events. Small molecule inhibitors that are promiscuous are of limited use, given the complexities associated with understanding their overall cellular response in the context of a single target. Even small molecules that inhibit a reasonable number of cellular targets (< 10) can be plagued by a lack of certainty in terms of phenotype association to a single target. As such, we endeavored to further optimize NCGC00010037 (CID 3232621) (<b>2</b>) for specific inhibition of Clk4.</p></div><div id="ml167.s4"><h2 id="_ml167_s4_">2. Materials and Methods</h2><p><b>General Methods for Chemistry:</b> All air or moisture sensitive reactions were performed under positive pressure of nitrogen with oven-dried glassware. Anhydrous solvents such as dichloromethane, <i>N,N</i>-dimethylforamide (DMF), acetonitrile, methanol and triethylamine were obtained by purchasing from Sigma-Aldrich. Preparative purification was performed on a Waters semi-preparative HPLC. The column used was a Phenomenex Luna C18 (5 micron, 30× 75mm) at a flow rate of 45 ml/min. The mobile phase consisted of acetonitrile and water (each containing 0.1% trifluoroacetic acid). A gradient of 10% to 50% acetonitrile over 8 minutes was used during the purification. Fraction collection was triggered by UV detection (220nM). Analytical analysis was performed on an Agilent LC/MS (Agilent Technologies, Santa Clara, CA).</p><p>Method 1: A 7 minute gradient of 4% to 100% Acetonitrile (containing 0.025% trifluoroacetic acid) in water (containing 0.05% trifluoroacetic acid) was used with an 8 minute run time at a flow rate of 1 ml/min. A Phenomenex Luna C18 column (3 micron, 3× 75mm) was used at a temperature of 50°C.</p><p>Method 2: A 3 minute gradient of 4% to 100% Acetonitrile (containing 0.025% trifluoroacetic acid) in water (containing 0.05% trifluoroacetic acid) was used with a 4.5 minute run time at a flow rate of 1 ml/min. A Phenomenex Gemini Phenyl column (3 micron, 3× 100mm) was used at a temperature of 50°C.</p><p>Purity determination was performed using an Agilent Diode Array Detector on both Method 1 and Method 2. Mass determination was performed using an Agilent 6130 mass spectrometer with electrospray ionization in the positive mode. <sup>1</sup>H NMR spectra were recorded on Varian 400 MHz spectrometers. Chemical Shifts are reported in ppm with tetramethylsilane (TMS) as internal standard (0 ppm) for CDCl<sub>3</sub> solutions or undeuterated solvent (DMSO-h6 at 2.49 ppm) for DMSO-d6 solutions. All of the analogs for assay have purity greater than 95% based on both analytical methods. High resolution mass spectrometry was recorded on an Agilent 6210 Time-of-Flight LC/MS system. Confirmation of molecular formula was accomplished using electrospray ionization in the positive mode with the Agilent Masshunter software (version B.02).</p><div id="ml167.s5"><h3>2.1. Assays</h3><p>The application of bioluminescence to ATPases assay has relied on a substrate depletion format. In these assays, the ATP dependence of firefly luciferase is used to measure the remaining ATP concentration, where the luminescence signal is inversely proportional to kinase activity<a class="bibr" href="#ml167.r14" rid="ml167.r14 ml167.r15 ml167.r16 ml167.r17">14–17</a>. To provide a signal-to-background of approximately 2-fold, the substrate must be depleted by at least 50%. Operating enzyme assays under these high conversion conditions is not at all optimal for classical enzymological studies. However, this is acceptable for HTS, as shifts in potency are typically less than 2-fold with a percent conversion < 80%. Given that HTS assays typically show variability in potency determinations between ~2-3-fold, shifts due to high conversions in the range of 50–80%, will not be easily discernable from the assay noise even if the assay is performed at lower conversions. Therefore, ATP-depletion has become a popular choice to perform generic HTS assays for ATPases, particularly protein kinases.</p><p>We used two bioluminescent assays for the Clk4 assay (<a class="figpopup" href="/books/NBK56236/figure/ml167.f2/?report=objectonly" target="object" rid-figpopup="figml167f2" rid-ob="figobml167f2">Figure 2</a>). Measurement of ATP depletion was assessed by using the Kinase-Glo™ assay system, where a firefly luciferase detection reagent containing D-luciferin and buffer components are added to detect the remaining ATP, following the Clk4 kinase assay (<a class="figpopup" href="/books/NBK56236/figure/ml167.f2/?report=objectonly" target="object" rid-figpopup="figml167f2" rid-ob="figobml167f2">Figure 2A</a>). The second system, ADP-Glo<sup>®</sup> measures kinase activity by quantifying the amount of ADP formed after the kinase reaction. Bioluminescent detection of ADP levels is achieved through the addition two different detection reagents (<a class="figpopup" href="/books/NBK56236/figure/ml167.f2/?report=objectonly" target="object" rid-figpopup="figml167f2" rid-ob="figobml167f2">Figure 2B</a>). First, a reagent that stops the protein kinase reaction and depletes the remaining ATP is added. Then, a second reagent is added to stop ATP degradation. In addition, the second reagent also contains an enzyme, such as pyruvate kinase, that efficiently converts the ADP to ATP and the same firefly luciferase/D-luciferin components present in Kinase-Glo, which generate the luminescent signal proportional to the ADP concentration produced. Therefore, the two assay formats show opposite luminescent signal changes in response to protein kinase inhibitors.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml167f2" co-legend-rid="figlgndml167f2"><a href="/books/NBK56236/figure/ml167.f2/?report=objectonly" target="object" title="Figure 2" class="img_link icnblk_img figpopup" rid-figpopup="figml167f2" rid-ob="figobml167f2"><img class="small-thumb" src="/books/NBK56236/bin/ml167f2.gif" src-large="/books/NBK56236/bin/ml167f2.jpg" alt="Figure 2. Bioluminescent assays used for Clk4 qHTS." /></a><div class="icnblk_cntnt" id="figlgndml167f2"><h4 id="ml167.f2"><a href="/books/NBK56236/figure/ml167.f2/?report=objectonly" target="object" rid-ob="figobml167f2">Figure 2</a></h4><p class="float-caption no_bottom_margin">Bioluminescent assays used for Clk4 qHTS. <i>A</i>. Bioluminescent measurement of ATP depletion using Kinase-Glo. <i>B</i>. Bioluminescent measurement of ADP formation using ADP-Glo. </p></div></div><p>All compounds were screened using a qHTS approach<a class="bibr" href="#ml167.r14" rid="ml167.r14">14</a>, where compounds are assayed using at least seven concentrations to generate concentration-response curves for every compounds. The methodology for creating a concentration-titration series between successive copies of library plates for the purpose of large-scale titration-based screening has been described. Briefly, qHTS uses an inter-plate dilution method where the first plate contains the highest concentration of a set of compounds in DMSO, while subsequent plates contain the same compounds in the same well locations, but at successive lower concentrations. Using the protocol outlined above, we calculated a plate throughput of 18 plates/hr, or approximately 7 samples/sec, on the Kalypsys robotic system, which means that a 7 point CRC was obtained every second on the robotic system.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml167t1"><a href="/books/NBK56236/table/ml167.t1/?report=objectonly" target="object" title="Table 1" class="img_link icnblk_img figpopup" rid-figpopup="figml167t1" rid-ob="figobml167t1"><img class="small-thumb" src="/books/NBK56236/table/ml167.t1/?report=thumb" src-large="/books/NBK56236/table/ml167.t1/?report=previmg" alt="Table 1. Assay protocol: The optimized 1536-well protocol." /></a><div class="icnblk_cntnt"><h4 id="ml167.t1"><a href="/books/NBK56236/table/ml167.t1/?report=objectonly" target="object" rid-ob="figobml167t1">Table 1</a></h4><p class="float-caption no_bottom_margin">Assay protocol: The optimized 1536-well protocol. </p></div></div><p>The assay showed excellent performance (the signal-to-background ratio was 3.2 +/− 0.07, the average Z′ screening factor associated with each plate was 0.86 +/− 0.02 and the CV was 7.2 +/− 1.9, indicating a robust performance of the screen).</p><p>Additional assays were performed by commercial vendors, including Reaction Biology (<a href="http://www.reactionbiology.com" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.reactionbiology.com</a>) and Ambit Biosciences (<a href="http://www.ambitbio.com" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.ambitbio.com</a>). Reaction Biology relies upon a <sup>33</sup>P-γ-ATP radiometric based filtration binding assay, and the Ambit assay is based upon a competition binding assay of kinases fused to a proprietary tag.</p></div><div id="ml167.s6"><h3>2.2. Probe Chemical Characterization</h3><div id="ml167.f8" class="figure bk_fig"><div class="graphic"><img src="/books/NBK56236/bin/ml167f8.jpg" alt="Scheme 1. Reagents and conditions." /></div><h3><span class="label">Scheme 1</span><span class="title">Reagents and conditions</span></h3><div class="caption"><p>(i) Pd(PPh<sub>3</sub>)<sub>4</sub>, Na<sub>2</sub>CO<sub>3</sub>, DME, H<sub>2</sub>O, 150 °C (MW), 1.5 h (typical yields: 40–50%); (ii) POCl<sub>3</sub>, N,N-dimethylaniline, toluene, reflux, 1 h; (iii) DIPEA, DMF, rt, 2 h (typical yields: 80–95%); (iv) LAH, THF, rt, 15 min (typical yields: 80–95%)</p></div></div><p><b>NCGC00188654/CID 44968231/<a href="/pcsubstance/?term=ML167[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML167</a></b>: 1H NMR (400 MHz, DMSO-d6) δ 8.79 – 8.93 (2 H, m), 8.69 – 8.79 (1 H, m), 8.22 – 8.36 (1 H, m), 7.75 – 7.91 (1 H, m), 6.99 – 7.16 (1 H, m), 6.48 – 6.60 (1 H, m), 6.26 – 6.38 (1 H, m), 6.01 – 6.12 (1 H, m), 4.88 (2 H, br. s.), 4.51 (2 H, br. s.), 2.24 (3 H, br. s.). LC/MS: Method 1, retention time: 2.865 min; Method 2, retention time: 3.917 min. HRMS: m/z (M+H) = 336.1343 (Calculated for C19H18N3O3 336.1348). Solubility (PBS, pH 7.4, 23°C) = 20.1μM. Stability profile over 48 hrs (PBS, pH 7.4, 23°C) is shown below.</p><div id="ml167.f3a" class="figure bk_fig"><div class="graphic"><img src="/books/NBK56236/bin/ml167f3a.jpg" alt="Stability (PBS Buffer @ pH 7.4)." /></div><h3><span class="title">Stability (PBS Buffer @ pH 7.4)</span></h3></div><div id="ml167.f3" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%203.%20LCMS%20traces%20of%20NCGC00188654%2FCID%2044968231%2FML167%20in%20PBS%20buffer%2C%20pH%207.4%20at%2023%B0C%20at%200%20hours%20and%2048%20hours.&p=BOOKS&id=56236_ml167f3.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK56236/bin/ml167f3.jpg" alt="Figure 3. LCMS traces of NCGC00188654/CID 44968231/ML167 in PBS buffer, pH 7.4 at 23°C at 0 hours and 48 hours." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 3</span><span class="title">LCMS traces of NCGC00188654/CID 44968231/<a href="/pcsubstance/?term=ML167[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML167</a> in PBS buffer, pH 7.4 at 23°C at 0 hours and 48 hours</span></h3></div><div id="ml167.s7"><h4>MLS Numbers for Probe and Analogs</h4><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml167tu2"><a href="/books/NBK56236/table/ml167.tu2/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figml167tu2" rid-ob="figobml167tu2"><img class="small-thumb" src="/books/NBK56236/table/ml167.tu2/?report=thumb" src-large="/books/NBK56236/table/ml167.tu2/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ml167.tu2"><a href="/books/NBK56236/table/ml167.tu2/?report=objectonly" target="object" rid-ob="figobml167tu2">Table</a></h4></div></div></div></div><div id="ml167.s8"><h3>2.3. Probe Preparation</h3><p>The production of <i>N</i>-substituted-6-arylquinazolin-4-amines can be accomplished via two similar synthetic approaches. The synthesis of NCGC00010037 (CID 3232621) (<b>2</b>) was accomplished via the addition of thiophen-2-ylmethanamine to 6-bromo-4-chloroquinazoline in DMF with Hunig’s base at room temperature. The resulting product was then subjected to standard Suzuki-Miyaura couplings with benzo[d][1,3]dioxol-5-ylboronic acid using tetrakis(triphenylphosphine)palladium(0) and sodium carbonate in DMF and heating using microwave irradiation. This general procedure resulted in the production of numerous <i>N</i>-substituted-6-arylquinazolin-4-amines. Alternatively, the synthesis of NCGC00188654 (CID 44968231) began with the Suzuki-Miyaura coupling of 6-bromoquinazolin-4(3H)-one (<b>3</b>) to 5-(ethoxycarbonyl)furan-2-ylboronic acid. The resulting ethyl 5-(4-oxo-3,4-dihydroquinazolin-6-yl)furan-2-carboxylate (<b>4</b>) was treated with POCl<sub>3</sub> to derive ethyl 5-(4-chloroquinazolin-6-yl)furan-2-carboxylate (<b>5</b>). Addition of (5-methylfuran-2-yl)methanamine in basic DMF displaced the chlorine to arrive at ethyl 5-(4-((5-methylfuran-2-yl)methylamino)quinazolin-6-yl)furan-2-carboxylate (<b>6</b>), and a standard LAH reduction of the ethyl ester provided the probe compound (5-(4-((5-methylfuran-2-yl)methylamino)quinazolin-6-yl)furan-2-yl)methanol (NCGC00188654, CID 44968231)(<b>7</b>) in good overall yield.</p></div></div><div id="ml167.s9"><h2 id="_ml167_s9_">3. Results</h2><p>The identification of these agents as potent inhibitors of Clk1, Clk4, Dyrk1A and Dyrk1B was discovered following their assessment in a cell-based assay aimed at identifying modulators of Lamin A splicing. As the assay description (found in PubChem) describes:</p><blockquote><p>“Hutchinson-Gilford Progeria Syndrome (HGPS) is a pediatric premature aging disease caused by a spontaneous mutation in the lamin A/C (LMNA) gene. The mutation activates a cryptic splice site in the LMNA pre-mRNA which results in production of a pre-lamin A protein that cannot be processed properly. The mutant protein accumulates in the nucleus and negatively affects numerous cellular functions. Correction of the splicing defect in HGPS patient cells using a targeted oligonucleotide (exo11) leads to reversal of the cellular disease phenotypes. To identify small molecule modulators of aberrant LMNA splicing, a homogenous assay was constructed in HeLa cells that used a GFP containing minigene to report on correction of aberrant splicing in lamin A and a RFP (DsRed2) to report on cell viability, uniformity and nonspecific effects on the assay signal.”</p></blockquote><p>The discovery of quinoline-based agents as putative actives in this screen strongly suggested kinase activity as a mechanism by which the splicing correction was being manifested. A literature search uncovered the Cdc2-like kinase (Clk) family as a modifier of the prominent family of serine- and arginine-rich (SR) splicing proteins. Examination of the lead compounds in a Clk4 assay found that these agents were indeed capable of potent inhibition of the target. Following this realization, we aimed to optimize this compound class for potent and selective inhibition of the Clk class of kinases. During a selectivity examination of several of these compounds, we discovered that these compounds were further capable of inhibiting the Dyrk class of kinases, which are also implicated in splicing modulation via the phosphorylation of the splicing factor SF3b1. At the present time, agents have been discovered with activity at Clk4, Clk1, Dyrk1A and Dyrk1B (with varying degrees of selectivity). These agents represent the largest collection of Clk and Dyrk inhibitors, and several boast the best reported potency for these targets. The mechanism of action strongly suggests that these are ATP-competitive kinase inhibitors, which is in alignment with other known quinazoline-based kinases inhibitors, and molecular dynamic simulations and modeling support this assessment. Several cell-based assays are now being examined to establish these compounds (and the role of their targets) in broader phenotypical outcomes, including the role of the Clk and Dyrk kinases as modulators of gene splicing.</p><div id="ml167.s10"><h3>3.1. Summary of Screening Results</h3><p>Not applicable (the activity at Clk4 and related kinases was uncovered from leads found in the qHTS Assay for Modulators of Lamin A Splicing; <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1487" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 1487</a>).</p><div id="ml167.s11"><h4>Identification of lead</h4><p>This screening effort revealed several small molecule Clk4 inhibitors within the high confidence 1a, 1b and 2c concentration-response curves (CRCs; class 1 curves display two asymptotes, an inflection point, and r<sup>2</sup> ≥0.9; subclasses 1a and 1b are differentiated by full (>80%) vs. partial (≤ 80%) response, respectively, while class 2a curves display a single left-hand asymptote and inflection point and full (>80%) response)<a class="bibr" href="#ml167.r17" rid="ml167.r17">17</a>. A cheminformatics analysis of the qHTS data included chemotype clustering, singleton identification, analysis of orthogonal activities, and structural considerations, which included physical properties and anticipated optimization potential. Potency range and maximum response was additionally considered. Ultimately, this analysis led us to focus on the substituted quinazoline NCGC00010947 (CID 3233528) (<b>8</b>) (<a class="figpopup" href="/books/NBK56236/figure/ml167.f4/?report=objectonly" target="object" rid-figpopup="figml167f4" rid-ob="figobml167f4">Figure 4</a>). Our first rounds of synthesis and evaluation identified NCGC00010037 (CID 3232621) (<b>9</b>) as a potent Clk1, Clk4 and Dyrk1A inhibitor.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml167f4" co-legend-rid="figlgndml167f4"><a href="/books/NBK56236/figure/ml167.f4/?report=objectonly" target="object" title="Figure 4" class="img_link icnblk_img figpopup" rid-figpopup="figml167f4" rid-ob="figobml167f4"><img class="small-thumb" src="/books/NBK56236/bin/ml167f4.gif" src-large="/books/NBK56236/bin/ml167f4.jpg" alt="Figure 4. Structure of NCGC00010947 (8) and NCGC00010037 (9)." /></a><div class="icnblk_cntnt" id="figlgndml167f4"><h4 id="ml167.f4"><a href="/books/NBK56236/figure/ml167.f4/?report=objectonly" target="object" rid-ob="figobml167f4">Figure 4</a></h4><p class="float-caption no_bottom_margin">Structure of NCGC00010947 (<i>8</i>) and NCGC00010037 (<i>9</i>). </p></div></div></div></div><div id="ml167.s12"><h3>3.2. Dose Response Curves for Probe</h3><div id="ml167.f5" class="figure bk_fig"><div class="graphic"><img src="/books/NBK56236/bin/ml167f5.jpg" alt="Figure 5. Structure of NCGC00188654/CID 44968231/ML167 and dose response curve for in-house Clk4 assay." /></div><h3><span class="label">Figure 5</span><span class="title">Structure of NCGC00188654/CID 44968231/<a href="/pcsubstance/?term=ML167[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML167</a> and dose response curve for in-house Clk4 assay</span></h3></div></div><div id="ml167.s13"><h3>3.3. Scaffold/Moiety Chemical Liabilities</h3><p>NCGC00188654/CID 44968231/<a href="/pcsubstance/?term=ML167[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML167</a> contains a furan ring which may be liable to <i>in vivo</i> metabolism.</p></div><div id="ml167.s14"><h3>3.4. SAR Tables</h3><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml167t2"><a href="/books/NBK56236/table/ml167.t2/?report=objectonly" target="object" title="Table 2" class="img_link icnblk_img figpopup" rid-figpopup="figml167t2" rid-ob="figobml167t2"><img class="small-thumb" src="/books/NBK56236/table/ml167.t2/?report=thumb" src-large="/books/NBK56236/table/ml167.t2/?report=previmg" alt="Table 2. Inhibition at Clk1-4 and Dyrk1A and Dyrk1B for selected quinazoline based Clk4 inhibitors." /></a><div class="icnblk_cntnt"><h4 id="ml167.t2"><a href="/books/NBK56236/table/ml167.t2/?report=objectonly" target="object" rid-ob="figobml167t2">Table 2</a></h4><p class="float-caption no_bottom_margin">Inhibition at Clk1-4 and Dyrk1A and Dyrk1B for selected quinazoline based Clk4 inhibitors. </p></div></div></div><div id="ml167.s15"><h3>3.5. Cellular Activity</h3><p>Cellular studies have not yet been run with these agents.</p></div><div id="ml167.s16"><h3>3.6. Profiling Assays</h3><p>NCGC00188654/CID 44968231/<a href="/pcsubstance/?term=ML167[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML167</a> has been run in Ambit’s KinomeScan profile of 442 kinases. Language from the Ambit report describes the technology:</p><blockquote><p>“KINOME<i>scan</i>™ is based on a competition binding assay that quantitatively measures the ability of a compound to compete with an immobilized, active-site directed ligand. The assay is performed by combining three components: DNA-tagged kinase; immobilized ligand; and a test compound. The ability of the test compound to compete with the immobilized ligand is measured via quantitative PCR of the DNA tag. The compound(s) were screened at the concentration(s) requested, and results for primary screen binding interactions are reported as ‘% Ctrl’, where lower numbers indicate stronger hits in the matrix on the following page(s).”</p></blockquote><p>Activities below a 10% threshold are currently being profiled for Kd values versus those targets. We further analyzed NCGC00188654/CID 44968231/<a href="/pcsubstance/?term=ML167[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML167</a> for cell permeability in a commercially available Caco-2 assay. The Papp (A2B) was 32.0 with a percent recovery of 81.4% and the Papp (B2A) was 24.7 with a percent recovery of 81.2%. Atenolol (50% human absorption) and propranolol (90% human absorption) were used as a guide for ranking compounds in terms of permeability. Based on the values for these control compounds, the results for NCGC00188654/CID 44968231/<a href="/pcsubstance/?term=ML167[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML167</a> suggest that this agent will be highly cell permeable.</p></div></div><div id="ml167.s17"><h2 id="_ml167_s17_">4. Discussion</h2><p>This report details a novel class of Clk inhibitors based upon a core 6-arylquinazolin-4-amine scaffold. Selected agents were screened versus Clk4 to gain an appreciation of this chemotype’s SAR, and selected agents were found to inhibit this enzyme with potencies below 100nM. One early-stage analogue (<b>2</b>) was profiled against a panel of over 400 kinases and found to be remarkably selective for Clk1, Clk4 and Dyrk1A. The only other reported inhibitor of the Clk family [TG003 (<b>1</b>)] was also profiled and found to bind selectively to Clk1, Clk2, Clk4 and Dyrk1A. Analysis of the mechanism of action highly suggests that this chemotype inhibits Clk4 via competition with ATP binding. Molecular modeling also suggests that <b>2</b> and related agents inhibit the Clk isozymes through binding at the ATP binding domain. Further SAR evaluations have found newer agents with enhanced potency and selectivity profiles, including NCGC00188654/CID 44968231/<a href="/pcsubstance/?term=ML167[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML167</a> (<b>7</b>), which we define as a probe of Clk4. These agents provide useful tools for the study of Clk1, Clk4 and Dyrk1A and their respective roles in pre-mRNA splicing.</p><div id="ml167.s18"><h3>4.1. Comparison to existing art and how the new probe is an improvement</h3><p>NCGC00188654/CID 44968231/<a href="/pcsubstance/?term=ML167[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML167</a> (<b>7</b>) is a more selective inhibitor of Clk4 when compared to NCGC00010037/CID 3232621)(<b>2</b>) and TG0003 (<b>1</b>).</p></div><div id="ml167.s19"><h3>4.2. Mechanism of Action Studies</h3><p>We explored the binding modality of this chemotype by examining the inhibitory capacity of NCGC00010037/CID 3232621/<a href="https://pubchem.ncbi.nlm.nih.gov/substance/85239684" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 85239684</a> (<b>2</b>) in settings that varied both compound and substrate concentrations. The dose response curve of <b>2</b> in the presence of 3 different ATP concentrations demonstrated a loss in potency when ATP levels rose (<a class="figpopup" href="/books/NBK56236/figure/ml167.f6/?report=objectonly" target="object" rid-figpopup="figml167f6" rid-ob="figobml167f6">Figure 6</a>). Conversely, the percent activity of <b>1</b> in the presence of varying concentrations of the peptide substrate had no affect on the compound potency. This data highly suggests that NCGC00010037/CID 3232621 (<b>2</b>) is an ATP-competitive inhibitor of Clk4. Based upon the similarity of NCGC00188654/CID 44968231/<a href="/pcsubstance/?term=ML167[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML167</a>, it is expected that this agent is also an ATP-competitive inhibitor of Clk4.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml167f6" co-legend-rid="figlgndml167f6"><a href="/books/NBK56236/figure/ml167.f6/?report=objectonly" target="object" title="Figure 6" class="img_link icnblk_img figpopup" rid-figpopup="figml167f6" rid-ob="figobml167f6"><img class="small-thumb" src="/books/NBK56236/bin/ml167f6.gif" src-large="/books/NBK56236/bin/ml167f6.jpg" alt="Figure 6. A." /></a><div class="icnblk_cntnt" id="figlgndml167f6"><h4 id="ml167.f6"><a href="/books/NBK56236/figure/ml167.f6/?report=objectonly" target="object" rid-ob="figobml167f6">Figure 6</a></h4><p class="float-caption no_bottom_margin">A. Inhibitory dose response of <i>2</i> in the presence of three different ATP concentrations [1μM (filled circles), 50μM (empty circles), 100μM (empty squares)]. B. Inhibitory dose response of <i>2</i> in the presence of three different peptide <a href="/books/NBK56236/figure/ml167.f6/?report=objectonly" target="object" rid-ob="figobml167f6">(more...)</a></p></div></div><p>Following confirmation that this chemotype inhibits Clk4 via an ATP competitive mechanism, it was of interest to explore docking of <b>2</b> at a Clk kinase. As previously mentioned, quinazoline-based small molecules have precedence as kinase inhibitors. Among these reagents is the clinically approved drug erlotinib (Tarceva ®). Erlotinib is currently indicated for treatment of non-small cell lung and pancreatic cancer, and its actions are mediated through inhibition of the EGFR tyrosine kinase. In 2002, Stamos <i>et al</i> reported the structure of erlotinib bound to the ATP binding domain of EGFR (PDB code: 1M17). We theorized that the relationship of the 4-anilinoquinazoline structure of erlotinib to our newly discovered Clk family inhibitors may provide significant insight into the binding modality and mechanism of action for this class of compounds. There are no published X-ray structures of Clk4. There are structures of Clk1 (PDB code: 1Z57) and Clk3 (PDB code: 2EU9). Clk1 and Clk4 are highly homologous enzymes (>85% sequence identity), while Clk2 and Clk3 also share a high degree of sequence homology (>70% sequence identity). Based upon this, we utilized the X-ray structure of Clk1 as the template to derive a homology model of Clk4 using MOE molecular modeling software<a class="bibr" href="#ml167.r18" rid="ml167.r18">18</a>. Molecular docking was performed on <b>2</b> within the ATP binding domain of Clk1 and Clk4 to achieve an optimal binding pose using FRED (<a class="figpopup" href="/books/NBK56236/figure/ml167.f7/?report=objectonly" target="object" rid-figpopup="figml167f7" rid-ob="figobml167f7">Figure 7</a>). In the crystal structure of erlotinib and EGFR, the N1 of the quinalozine heterocycle makes a critical H-bond to an amide NH of the hinge region of the ATP binding pocket. This interaction is mimicked within our docking analysis of <b>2</b> at Clk1 and Clk4. The thiophen-2-ylmethanamine moiety is oriented to fill an open pocket formed by the gatekeeper Phe241 (Phe239 in Clk4), while the benzo[d][1,3]dioxole extends toward the solvent exposed face of the hinge region. While this model partially accounts for various aspects of the SAR found to date, more extensive exploration of this binding modality is required to fully understand the potency and remarkable selectivity associated with this chemotype.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml167f7" co-legend-rid="figlgndml167f7"><a href="/books/NBK56236/figure/ml167.f7/?report=objectonly" target="object" title="Figure 7" class="img_link icnblk_img figpopup" rid-figpopup="figml167f7" rid-ob="figobml167f7"><img class="small-thumb" src="/books/NBK56236/bin/ml167f7.gif" src-large="/books/NBK56236/bin/ml167f7.jpg" alt="Figure 7. Docking model of 2 in the Clk1 catalytic cleft." /></a><div class="icnblk_cntnt" id="figlgndml167f7"><h4 id="ml167.f7"><a href="/books/NBK56236/figure/ml167.f7/?report=objectonly" target="object" rid-ob="figobml167f7">Figure 7</a></h4><p class="float-caption no_bottom_margin">Docking model of <i>2</i> in the Clk1 catalytic cleft. The binding pocket is depicted by molecular surface in mesh grey and the hydrogen bonds are labeled as green dotted lines. This figure was prepared with the program VIDA (OpenEye Scientific Software). </p></div></div></div><div id="ml167.s20"><h3>4.3. Planned Future Studies</h3><p>With good probes defined versus Clk4 (NCGC00188654/CID 44968231/<a href="/pcsubstance/?term=ML167[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML167</a> (<b>7</b>)), Clk1/4 (NCGC00185963/CID 44223952), Dyrk1A (NCGC00229610/CID 469161787) and Dyrk1B (NCGC00185981/CID 44223970), we now intend to pursue collaborations to examine these agents in a variety of systems. Our first publication has already generated interested collaborators. For instance, a potential collaboration has been proposed surrounding the use of splicing modulators in the study of Spinal Muscular Atrophy (SMA). SMA is a severe congenital neurological disorder and a leading cause of mortality in infants and toddlers. There are approximately 50,000 patients in the US, EU and Japan. The disease is characterized by progressive loss of motor neurons so patients lose the ability to walk, stand and move. Respiratory insufficiency is often fatal. The single known cause of SMA is mutations in SMN1, which encodes a protein involved in spliceosome assembly. Clk kinases regulate alternative splicing and so the modulation of these kinases pharmacologically may address functional deficiencies in SMA. Assistive technologies such as ventilators have improved the lives of SMA patients, but there are currently no approved therapeutic options for this condition.</p></div></div><div id="ml167.s21"><h2 id="_ml167_s21_">Probe properties</h2><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml167tu3"><a href="/books/NBK56236/table/ml167.tu3/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figml167tu3" rid-ob="figobml167tu3"><img class="small-thumb" src="/books/NBK56236/table/ml167.tu3/?report=thumb" src-large="/books/NBK56236/table/ml167.tu3/?report=previmg" alt="Properties computed from Structure." /></a><div class="icnblk_cntnt"><h4 id="ml167.tu3"><a href="/books/NBK56236/table/ml167.tu3/?report=objectonly" target="object" rid-ob="figobml167tu3">Table</a></h4><p class="float-caption no_bottom_margin">Properties computed from Structure. </p></div></div></div><div id="ml167.s22"><h2 id="_ml167_s22_">5. References</h2><dl class="temp-labeled-list"><dl class="bkr_refwrap"><dt>1.</dt><dd><div class="bk_ref" id="ml167.r1">Krämer A. <span><span class="ref-journal">Annu. Rev. Biochem. </span>1996;<span class="ref-vol">65</span>:367–409.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/8811184" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8811184</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>2.</dt><dd><div class="bk_ref" id="ml167.r2">Black DL. <span><span class="ref-journal">Annu. Rev. Biochem. </span>2003;<span class="ref-vol">72</span>:291–336.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12626338" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12626338</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>3.</dt><dd><div class="bk_ref" id="ml167.r3">Faustino NA, Cooper TA. <span><span class="ref-journal">Genes Dev. </span>2003;<span class="ref-vol">17</span>:419–437.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12600935" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12600935</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>4.</dt><dd><div class="bk_ref" id="ml167.r4">Hanes J, von der Kammer H, Klaudiny J, Scheit KH. <span><span class="ref-journal">J. Mol. Biol. </span>1994;<span class="ref-vol">244</span>:665–672.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/7990150" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7990150</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>5.</dt><dd><div class="bk_ref" id="ml167.r5">Nayler O, Stamm S, Ullrich A. <span><span class="ref-journal">Biochem. J. </span>1997;<span class="ref-vol">326</span>:693–700.</span> [<a href="/pmc/articles/PMC1218723/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1218723</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/9307018" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9307018</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>6.</dt><dd><div class="bk_ref" id="ml167.r6">Prasad J, Manley JL. <span><span class="ref-journal">Mol. Cell. Biol. </span>2003;<span class="ref-vol">23</span>:4139–4149.</span> [<a href="/pmc/articles/PMC156123/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC156123</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/12773558" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12773558</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>7.</dt><dd><div class="bk_ref" id="ml167.r7">Manley JL, Tacke R. <span><span class="ref-journal">Genes Dev. </span>1996;<span class="ref-vol">10</span>:1569–1579.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/8682289" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8682289</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>8.</dt><dd><div class="bk_ref" id="ml167.r8">Zahler AM, Lane WS, Stolk JA, Roth MB. <span><span class="ref-journal">Genes Dev. </span>1992;<span class="ref-vol">6</span>:837–847.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/1577277" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 1577277</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>9.</dt><dd><div class="bk_ref" id="ml167.r9">Hagiwara M. <span><span class="ref-journal">Biochemica et Biophysica Acta. </span>2005;<span class="ref-vol">1754</span>:324–331.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16260193" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16260193</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>10.</dt><dd><div class="bk_ref" id="ml167.r10">Mott BT, Tanega C, Shen M, Maloney DJ, Shinn P, Leister W, Marugan JJ, Inglese J, Austin CP, Misteli T, Auld DS, Thomas CJ. <span><span class="ref-journal">Bioorg Med. Chem. Lett. </span>2009;<span class="ref-vol">19</span>:6700–6705.</span> [<a href="/pmc/articles/PMC2807730/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2807730</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19837585" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19837585</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>11.</dt><dd><div class="bk_ref" id="ml167.r11">Hartmann AM, Rujescu D, Giannakouros T, Nikolakaki E, Goedert M, Mandelkow E-M, Gao QS, Andreadis A, Stamm S. <span><span class="ref-journal">Mol. Cell. Neuro. </span>2001;<span class="ref-vol">18</span>:80–90.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11461155" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11461155</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>12.</dt><dd><div class="bk_ref" id="ml167.r12">Perni RB, Bemis J, Nunes JJ, Szczepankiewicz BG. Inhibitors of the CDC2-like Kinases and Methods of Use Therof. 2009/085226. <span><span class="ref-journal">WO. </span>2009 Jul 9;<span class="ref-vol">A2</span></span></div></dd></dl><dl class="bkr_refwrap"><dt>13.</dt><dd><div class="bk_ref" id="ml167.r13">Hekimi S, McBride K, Hihi AK, Kianjcka I, Wang Y, Hayes SL, Guimond M-P, Sevigny G, Dumas D, Smith J. 60/832937. <span><span class="ref-journal">New Quinoline Derivatives. </span>2006 Jul 25;</span></div></dd></dl><dl class="bkr_refwrap"><dt>14.</dt><dd><div class="bk_ref" id="ml167.r14">Fan F, Wood KV. <span><span class="ref-journal">Assay Drug Dev Technol. </span>2007;<span class="ref-vol">5</span>:127–36.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17355205" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17355205</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>15.</dt><dd><div class="bk_ref" id="ml167.r15">Schroter T, Minond D, Weiser A, Dao C, Habel J, Spicer T, Chase P, Baillargeon P, Scampavia L, Schurer S, Chung C, Mader C, Southern M, Tsinoremas N, LoGrasso P, Hodder P. <span><span class="ref-journal">J Biomol Screen. </span>2008;<span class="ref-vol">13</span>:17–28.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18227223" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18227223</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>16.</dt><dd><div class="bk_ref" id="ml167.r16">Singh P, Harden BJ, Lillywhite BJ, Broad PM. <span><span class="ref-journal">Assay Drug Dev Technol. </span>2004;<span class="ref-vol">2</span>:161–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15165512" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15165512</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>17.</dt><dd><div class="bk_ref" id="ml167.r17">Inglese J, Auld DS, Jadhav A, Johnson RL, Simeonov A, Yasgar A, Zheng W, Austin CP. Quantitative high-throughput screening: A titration-based approach that efficiently identifies biological activities in large chemical libraries. <span><span class="ref-journal">Proc Natl Acad Sci U.S.A. </span>2006;<span class="ref-vol">103</span>:11473–8.</span> [<a href="/pmc/articles/PMC1518803/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1518803</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/16864780" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16864780</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>18.</dt><dd><div class="bk_ref" id="ml167.r18"><span class="ref-journal">MOE Molecular Operating EnVironment, Version 2008.10.</span> Chemical Computing Group Inc; Montreal, Canada: 2008. </div></dd></dl></dl></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK56236_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><p class="contrib-group"><h4>Authors</h4><span itemprop="author">Andrew S Rosenthal</span>,<sup>a</sup> <span itemprop="author">Cordelle Tanega</span>,<sup>a</sup> <span itemprop="author">Min Shen</span>,<sup>a</sup> <span itemprop="author">Bryan T Mott</span>,<sup>a</sup> <span itemprop="author">James M Bougie</span>,<sup>a</sup> <span itemprop="author">Dac-Trung Nguyen</span>,<sup>a</sup> <span itemprop="author">Tom Misteli</span>,<sup>b</sup> <span itemprop="author">Douglas S Auld</span>,<sup>a</sup> <span itemprop="author">David J Maloney</span>,<sup>a</sup> and <span itemprop="author">Craig J Thomas</span><sup>a</sup>.</p><h4>Affiliations</h4><div class="affiliation"><sup>a</sup>
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NIH Chemical Genomics Center, National Human Genome Research Institute, NIH 9800 Medical Center Drive, MSC 3370 Bethesda, MD 20892-3370 USA</div><div class="affiliation"><sup>b</sup>
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Cell Biology of Genomes, National Cancer Institute, NIH, 41 Library Drive, Bethesda, MD 20892 USA</div><h3>Publication History</h3><p class="small">Received: <span itemprop="datePublished">March 29, 2010</span>; Last Update: <span itemprop="dateModified">March 3, 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>Rosenthal AS, Tanega C, Shen M, et al. An inhibitor of the Cdc2-like kinase 4 (Clk4) 2010 Mar 29 [Updated 2011 Mar 3]. 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/ml168/?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/ml165/?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="figobml167fu1"><div id="ml167.fu1" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK56236/bin/ml167fu1.jpg" alt="ML167." /></div><h3><span class="title"><a href="/pcsubstance/?term=ML167[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML167</a></span></h3></div></article><article data-type="table-wrap" id="figobml167tu1"><div id="ml167.tu1" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK56236/table/ml167.tu1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml167.tu1_lrgtbl__"><table><thead><tr><th id="hd_h_ml167.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CID/ML#</th><th id="hd_h_ml167.tu1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Target Name</th><th id="hd_h_ml167.tu1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">IC<sub>50</sub>/EC<sub>50</sub> (nM) [SID, AID]</th><th id="hd_h_ml167.tu1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Anti- target Name(s)</th><th id="hd_h_ml167.tu1_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">IC<sub>50</sub>/EC<sub>50</sub> (μM) [SID, AID]</th><th id="hd_h_ml167.tu1_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Fold Selective</th><th id="hd_h_ml167.tu1_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Secondary Assay(s) Name: IC<sub>50</sub>/EC<sub>50</sub> (nM) [SID, AID]</th></tr></thead><tbody><tr><td headers="hd_h_ml167.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">44968231/<a href="/pcsubstance/?term=ML167[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML167</a></td><td headers="hd_h_ml167.tu1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Cdc2- like kinase 4 (Clk4)</td><td headers="hd_h_ml167.tu1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">136nM [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/90944997" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">90944997</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2710" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2710</a>]</td><td headers="hd_h_ml167.tu1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Clk1, Clk2, Clk3, Dyrk1A/1 B</td><td headers="hd_h_ml167.tu1_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">>1μM [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/90944997" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">90944997</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2710" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2710</a>]</td><td headers="hd_h_ml167.tu1_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">>10 fold</td><td headers="hd_h_ml167.tu1_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Kinase panel [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/90944997" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">90944997</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2710" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2710</a>]</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobml167fu2"><div id="ml167.fu2" class="figure"><div class="graphic"><img data-src="/books/NBK56236/bin/ml167fu2.jpg" alt="Image ml167fu2" /></div></div></article><article data-type="fig" id="figobml167f1"><div id="ml167.f1" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK56236/bin/ml167f1.jpg" alt="Figure 1. Dendrogram representation of the selectivity profile for kinase binding by TG003 (1) and 2 within a panel of 402 kinases." /></div><h3><span class="label">Figure 1</span><span class="title">Dendrogram representation of the selectivity profile for kinase binding by TG003 (<b>1</b>) and <b>2</b> within a panel of 402 kinases</span></h3></div></article><article data-type="fig" id="figobml167fu3"><div id="ml167.fu3" class="figure"><div class="graphic"><img data-src="/books/NBK56236/bin/ml167fu3.jpg" alt="Image ml167fu3" /></div></div></article><article data-type="fig" id="figobml167f2"><div id="ml167.f2" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK56236/bin/ml167f2.jpg" alt="Figure 2. Bioluminescent assays used for Clk4 qHTS." /></div><h3><span class="label">Figure 2</span><span class="title">Bioluminescent assays used for Clk4 qHTS</span></h3><div class="caption"><p><b>A</b>. Bioluminescent measurement of ATP depletion using Kinase-Glo. <b>B</b>. Bioluminescent measurement of ADP formation using ADP-Glo.</p></div></div></article><article data-type="table-wrap" id="figobml167t1"><div id="ml167.t1" class="table"><h3><span class="label">Table 1</span><span class="title">Assay protocol: The optimized 1536-well protocol</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK56236/table/ml167.t1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml167.t1_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml167.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></th><th id="hd_h_ml167.t1_1_1_1_2" colspan="3" rowspan="1" style="text-align:center;vertical-align:top;">Kinase-Glo</th><th id="hd_h_ml167.t1_1_1_1_3" colspan="3" rowspan="1" style="text-align:center;vertical-align:top;">ADP-Glo</th></tr><tr><th headers="hd_h_ml167.t1_1_1_1_1 hd_h_ml167.t1_1_1_1_2 hd_h_ml167.t1_1_1_1_3" id="hd_h_ml167.t1_1_1_2_1" colspan="7" rowspan="1" style="text-align:center;vertical-align:bottom;">
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<span class="hr"></span></th></tr><tr><th headers="hd_h_ml167.t1_1_1_1_1 hd_h_ml167.t1_1_1_2_1" id="hd_h_ml167.t1_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Step</th><th headers="hd_h_ml167.t1_1_1_1_2 hd_h_ml167.t1_1_1_2_1" id="hd_h_ml167.t1_1_1_3_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parameter</th><th headers="hd_h_ml167.t1_1_1_1_2 hd_h_ml167.t1_1_1_2_1" id="hd_h_ml167.t1_1_1_3_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Value</th><th headers="hd_h_ml167.t1_1_1_1_2 hd_h_ml167.t1_1_1_2_1" id="hd_h_ml167.t1_1_1_3_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Description</th><th headers="hd_h_ml167.t1_1_1_1_3 hd_h_ml167.t1_1_1_2_1" id="hd_h_ml167.t1_1_1_3_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parameter</th><th headers="hd_h_ml167.t1_1_1_1_3 hd_h_ml167.t1_1_1_2_1" id="hd_h_ml167.t1_1_1_3_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Value</th><th headers="hd_h_ml167.t1_1_1_1_3 hd_h_ml167.t1_1_1_2_1" id="hd_h_ml167.t1_1_1_3_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Description</th></tr></thead><tbody><tr><td headers="hd_h_ml167.t1_1_1_1_1 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><b>1</b></td><td headers="hd_h_ml167.t1_1_1_1_2 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Reagent</td><td headers="hd_h_ml167.t1_1_1_1_2 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2μl</td><td headers="hd_h_ml167.t1_1_1_1_2 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">ATP/peptide</td><td headers="hd_h_ml167.t1_1_1_1_3 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Reagent</td><td headers="hd_h_ml167.t1_1_1_1_3 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2μl</td><td headers="hd_h_ml167.t1_1_1_1_3 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">ATP/peptide</td></tr><tr><td headers="hd_h_ml167.t1_1_1_1_1 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><b>2</b></td><td headers="hd_h_ml167.t1_1_1_1_2 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Library</td><td headers="hd_h_ml167.t1_1_1_1_2 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">23nl</td><td headers="hd_h_ml167.t1_1_1_1_2 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.5 nM- 46 μM</td><td headers="hd_h_ml167.t1_1_1_1_3 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Library</td><td headers="hd_h_ml167.t1_1_1_1_3 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">23nl</td><td headers="hd_h_ml167.t1_1_1_1_3 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.6 nM- 55.2 μM</td></tr><tr><td headers="hd_h_ml167.t1_1_1_1_1 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><b>3</b></td><td headers="hd_h_ml167.t1_1_1_1_2 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Controls</td><td headers="hd_h_ml167.t1_1_1_1_2 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">23nl</td><td headers="hd_h_ml167.t1_1_1_1_2 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">TG003</td><td headers="hd_h_ml167.t1_1_1_1_3 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Controls</td><td headers="hd_h_ml167.t1_1_1_1_3 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">23nl</td><td headers="hd_h_ml167.t1_1_1_1_3 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">TG003</td></tr><tr><td headers="hd_h_ml167.t1_1_1_1_1 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><b>4</b></td><td headers="hd_h_ml167.t1_1_1_1_2 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Reagent</td><td headers="hd_h_ml167.t1_1_1_1_2 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1μl</td><td headers="hd_h_ml167.t1_1_1_1_2 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Clk4</td><td headers="hd_h_ml167.t1_1_1_1_3 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Reagent</td><td headers="hd_h_ml167.t1_1_1_1_3 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.5μl</td><td headers="hd_h_ml167.t1_1_1_1_3 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Clk4</td></tr><tr><td headers="hd_h_ml167.t1_1_1_1_1 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><b>5</b></td><td headers="hd_h_ml167.t1_1_1_1_2 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Time</td><td headers="hd_h_ml167.t1_1_1_1_2 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">4.5 hrs</td><td headers="hd_h_ml167.t1_1_1_1_2 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">r.t. incubation</td><td headers="hd_h_ml167.t1_1_1_1_3 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Time</td><td headers="hd_h_ml167.t1_1_1_1_3 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 hr</td><td headers="hd_h_ml167.t1_1_1_1_3 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">r.t. incubation</td></tr><tr><td headers="hd_h_ml167.t1_1_1_1_1 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><b>6</b></td><td headers="hd_h_ml167.t1_1_1_1_2 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Reagent</td><td headers="hd_h_ml167.t1_1_1_1_2 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">3μl</td><td headers="hd_h_ml167.t1_1_1_1_2 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Kinase-Glo</td><td headers="hd_h_ml167.t1_1_1_1_3 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Reagent</td><td headers="hd_h_ml167.t1_1_1_1_3 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2.5μl</td><td headers="hd_h_ml167.t1_1_1_1_3 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Deplete ATP</td></tr><tr><td headers="hd_h_ml167.t1_1_1_1_1 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><b>7</b></td><td headers="hd_h_ml167.t1_1_1_1_2 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Read</td><td headers="hd_h_ml167.t1_1_1_1_2 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2 sec</td><td headers="hd_h_ml167.t1_1_1_1_2 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">ViewLux</td><td headers="hd_h_ml167.t1_1_1_1_3 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Time</td><td headers="hd_h_ml167.t1_1_1_1_3 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">45 min</td><td headers="hd_h_ml167.t1_1_1_1_3 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">r.t. incubation</td></tr><tr><td headers="hd_h_ml167.t1_1_1_1_1 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><b>8</b></td><td headers="hd_h_ml167.t1_1_1_1_2 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml167.t1_1_1_1_2 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml167.t1_1_1_1_2 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml167.t1_1_1_1_3 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Reagent</td><td headers="hd_h_ml167.t1_1_1_1_3 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">5μl</td><td headers="hd_h_ml167.t1_1_1_1_3 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">ADP→ATP/Luc</td></tr><tr><td headers="hd_h_ml167.t1_1_1_1_1 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><b>9</b></td><td headers="hd_h_ml167.t1_1_1_1_2 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml167.t1_1_1_1_2 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml167.t1_1_1_1_2 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml167.t1_1_1_1_3 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Time</td><td headers="hd_h_ml167.t1_1_1_1_3 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">30 min</td><td headers="hd_h_ml167.t1_1_1_1_3 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">r.t. incubation</td></tr><tr><td headers="hd_h_ml167.t1_1_1_1_1 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><b>10</b></td><td headers="hd_h_ml167.t1_1_1_1_2 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml167.t1_1_1_1_2 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml167.t1_1_1_1_2 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml167.t1_1_1_1_3 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Read</td><td headers="hd_h_ml167.t1_1_1_1_3 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2 sec</td><td headers="hd_h_ml167.t1_1_1_1_3 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">ViewLux</td></tr><tr><td headers="hd_h_ml167.t1_1_1_1_1 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_1 hd_h_ml167.t1_1_1_1_2 hd_h_ml167.t1_1_1_3_2 hd_h_ml167.t1_1_1_3_3 hd_h_ml167.t1_1_1_3_4 hd_h_ml167.t1_1_1_1_3 hd_h_ml167.t1_1_1_3_5 hd_h_ml167.t1_1_1_3_6 hd_h_ml167.t1_1_1_3_7" colspan="7" rowspan="1" style="text-align:left;vertical-align:top;">
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<span class="hr"></span></td></tr><tr><td headers="hd_h_ml167.t1_1_1_1_1 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Step</td><td headers="hd_h_ml167.t1_1_1_1_2 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_2 hd_h_ml167.t1_1_1_3_3 hd_h_ml167.t1_1_1_3_4" colspan="3" rowspan="1" style="text-align:left;vertical-align:top;">Notes</td><td headers="hd_h_ml167.t1_1_1_1_3 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_5 hd_h_ml167.t1_1_1_3_6 hd_h_ml167.t1_1_1_3_7" colspan="3" rowspan="1" style="text-align:left;vertical-align:top;">Notes</td></tr><tr><td headers="hd_h_ml167.t1_1_1_1_1 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_1 hd_h_ml167.t1_1_1_1_2 hd_h_ml167.t1_1_1_3_2 hd_h_ml167.t1_1_1_3_3 hd_h_ml167.t1_1_1_3_4 hd_h_ml167.t1_1_1_1_3 hd_h_ml167.t1_1_1_3_5 hd_h_ml167.t1_1_1_3_6 hd_h_ml167.t1_1_1_3_7" colspan="7" rowspan="1" style="text-align:left;vertical-align:top;">
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<span class="hr"></span></td></tr><tr><td headers="hd_h_ml167.t1_1_1_1_1 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><b>1</b></td><td headers="hd_h_ml167.t1_1_1_1_2 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_2 hd_h_ml167.t1_1_1_3_3 hd_h_ml167.t1_1_1_3_4" colspan="3" rowspan="1" style="text-align:left;vertical-align:top;">100μM RS peptide, 1μM ATP (final) concentration in buffer; FRD dispense</td><td headers="hd_h_ml167.t1_1_1_1_3 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_5 hd_h_ml167.t1_1_1_3_6 hd_h_ml167.t1_1_1_3_7" colspan="3" rowspan="1" style="text-align:left;vertical-align:top;">100μM RS peptide, 1μM ATP (final) concentration in buffer; FRD dispense</td></tr><tr><td headers="hd_h_ml167.t1_1_1_1_1 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><b>2</b></td><td headers="hd_h_ml167.t1_1_1_1_2 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_2 hd_h_ml167.t1_1_1_3_3 hd_h_ml167.t1_1_1_3_4" colspan="3" rowspan="1" style="text-align:left;vertical-align:top;">Pin-tool transfer compound library for a (final) range of 46μM to 0.5nM</td><td headers="hd_h_ml167.t1_1_1_1_3 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_5 hd_h_ml167.t1_1_1_3_6 hd_h_ml167.t1_1_1_3_7" colspan="3" rowspan="1" style="text-align:left;vertical-align:top;">Pin-tool transfer compound library for a (final) range of 55.2μM to 0.6nM</td></tr><tr><td headers="hd_h_ml167.t1_1_1_1_1 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><b>3</b></td><td headers="hd_h_ml167.t1_1_1_1_2 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_2 hd_h_ml167.t1_1_1_3_3 hd_h_ml167.t1_1_1_3_4" colspan="3" rowspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml167.t1_1_1_1_3 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_5 hd_h_ml167.t1_1_1_3_6 hd_h_ml167.t1_1_1_3_7" colspan="3" rowspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml167.t1_1_1_1_1 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><b>4</b></td><td headers="hd_h_ml167.t1_1_1_1_2 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_2 hd_h_ml167.t1_1_1_3_3 hd_h_ml167.t1_1_1_3_4" colspan="3" rowspan="1" style="text-align:left;vertical-align:top;">Clk4 at 25nM final, FRD dispense</td><td headers="hd_h_ml167.t1_1_1_1_3 hd_h_ml167.t1_1_1_2_1 hd_h_ml167.t1_1_1_3_5 hd_h_ml167.t1_1_1_3_6 hd_h_ml167.t1_1_1_3_7" colspan="3" rowspan="1" style="text-align:left;vertical-align:top;">Clk4 at 25nM final, FRD dispense</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobml167f8"><div id="ml167.f8" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK56236/bin/ml167f8.jpg" alt="Scheme 1. Reagents and conditions." /></div><h3><span class="label">Scheme 1</span><span class="title">Reagents and conditions</span></h3><div class="caption"><p>(i) Pd(PPh<sub>3</sub>)<sub>4</sub>, Na<sub>2</sub>CO<sub>3</sub>, DME, H<sub>2</sub>O, 150 °C (MW), 1.5 h (typical yields: 40–50%); (ii) POCl<sub>3</sub>, N,N-dimethylaniline, toluene, reflux, 1 h; (iii) DIPEA, DMF, rt, 2 h (typical yields: 80–95%); (iv) LAH, THF, rt, 15 min (typical yields: 80–95%)</p></div></div></article><article data-type="fig" id="figobml167f3a"><div id="ml167.f3a" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK56236/bin/ml167f3a.jpg" alt="Stability (PBS Buffer @ pH 7.4)." /></div><h3><span class="title">Stability (PBS Buffer @ pH 7.4)</span></h3></div></article><article data-type="fig" id="figobml167f3"><div id="ml167.f3" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%203.%20LCMS%20traces%20of%20NCGC00188654%2FCID%2044968231%2FML167%20in%20PBS%20buffer%2C%20pH%207.4%20at%2023%B0C%20at%200%20hours%20and%2048%20hours.&p=BOOKS&id=56236_ml167f3.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK56236/bin/ml167f3.jpg" alt="Figure 3. LCMS traces of NCGC00188654/CID 44968231/ML167 in PBS buffer, pH 7.4 at 23°C at 0 hours and 48 hours." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 3</span><span class="title">LCMS traces of NCGC00188654/CID 44968231/<a href="/pcsubstance/?term=ML167[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML167</a> in PBS buffer, pH 7.4 at 23°C at 0 hours and 48 hours</span></h3></div></article><article data-type="table-wrap" id="figobml167tu2"><div id="ml167.tu2" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK56236/table/ml167.tu2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml167.tu2_lrgtbl__"><table><thead><tr><th id="hd_h_ml167.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">NCGC ID</th><th id="hd_h_ml167.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MLS ID</th></tr></thead><tbody><tr><td headers="hd_h_ml167.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">NCGC00188654-01</td><td headers="hd_h_ml167.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MLS002729079 (Probe)</td></tr><tr><td headers="hd_h_ml167.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">NCGC00185966-01</td><td headers="hd_h_ml167.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MLS003179280</td></tr><tr><td headers="hd_h_ml167.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">NCGC00185976-01</td><td headers="hd_h_ml167.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MLS003179275</td></tr><tr><td headers="hd_h_ml167.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">NCGC00185985-01</td><td headers="hd_h_ml167.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MLS003179269</td></tr><tr><td headers="hd_h_ml167.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">NCGC00189261-01</td><td headers="hd_h_ml167.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MLS003179268</td></tr><tr><td headers="hd_h_ml167.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">NCGC00229611-01</td><td headers="hd_h_ml167.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MLS003179266</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobml167f4"><div id="ml167.f4" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK56236/bin/ml167f4.jpg" alt="Figure 4. Structure of NCGC00010947 (8) and NCGC00010037 (9)." /></div><h3><span class="label">Figure 4</span><span class="title">Structure of NCGC00010947 (<b>8</b>) and NCGC00010037 (<b>9</b>)</span></h3></div></article><article data-type="fig" id="figobml167f5"><div id="ml167.f5" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK56236/bin/ml167f5.jpg" alt="Figure 5. Structure of NCGC00188654/CID 44968231/ML167 and dose response curve for in-house Clk4 assay." /></div><h3><span class="label">Figure 5</span><span class="title">Structure of NCGC00188654/CID 44968231/<a href="/pcsubstance/?term=ML167[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML167</a> and dose response curve for in-house Clk4 assay</span></h3></div></article><article data-type="table-wrap" id="figobml167t2"><div id="ml167.t2" class="table"><h3><span class="label">Table 2</span><span class="title">Inhibition at Clk1-4 and Dyrk1A and Dyrk1B for selected quinazoline based Clk4 inhibitors</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK56236/table/ml167.t2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml167.t2_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml167.t2_1_1_1_1" colspan="7" rowspan="1" style="text-align:left;vertical-align:bottom;">
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<div class="graphic"><img src="/books/NBK56236/bin/ml167fu4.jpg" alt="Image ml167fu4.jpg" /></div></th><th id="hd_h_ml167.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Target</th><th id="hd_h_ml167.t2_1_1_1_3" colspan="5" rowspan="1" style="text-align:center;vertical-align:bottom;">Antitargets</th></tr><tr><th headers="hd_h_ml167.t2_1_1_1_1" id="hd_h_ml167.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">Entry</th><th headers="hd_h_ml167.t2_1_1_1_1" id="hd_h_ml167.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">NCGCID</th><th headers="hd_h_ml167.t2_1_1_1_1" id="hd_h_ml167.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">SID</th><th headers="hd_h_ml167.t2_1_1_1_1" id="hd_h_ml167.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">CID</th><th headers="hd_h_ml167.t2_1_1_1_1" id="hd_h_ml167.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">R<sub>1</sub></th><th headers="hd_h_ml167.t2_1_1_1_1" id="hd_h_ml167.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">R<sub>2</sub></th><th headers="hd_h_ml167.t2_1_1_1_1" id="hd_h_ml167.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">R<sub>3</sub></th><th headers="hd_h_ml167.t2_1_1_1_2" id="hd_h_ml167.t2_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">Clk4 IC<sub>50</sub> (nM)</th><th headers="hd_h_ml167.t2_1_1_1_3" id="hd_h_ml167.t2_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">Clk1 IC<sub>50</sub> (nM)</th><th headers="hd_h_ml167.t2_1_1_1_3" id="hd_h_ml167.t2_1_1_2_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">Clk2 IC<sub>50</sub> (nM)</th><th headers="hd_h_ml167.t2_1_1_1_3" id="hd_h_ml167.t2_1_1_2_11" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">Clk3 IC<sub>50</sub> (nM)</th><th headers="hd_h_ml167.t2_1_1_1_3" id="hd_h_ml167.t2_1_1_2_12" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">Dyrk1A IC<sub>50</sub> (nM)</th><th headers="hd_h_ml167.t2_1_1_1_3" id="hd_h_ml167.t2_1_1_2_13" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">Dyrk1B IC<sub>50</sub> (nM)</th></tr></thead><tbody><tr><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>2</b></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">00010037</td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85239684" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85239684</a></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3232621</td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>H</b></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK56236/bin/ml167fu5.jpg" alt="Image ml167fu5.jpg" /></div></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK56236/bin/ml167fu6.jpg" alt="Image ml167fu6.jpg" /></div></td><td headers="hd_h_ml167.t2_1_1_1_2 hd_h_ml167.t2_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>39</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>59</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>1902</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_11" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>6936</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_12" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>62</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_13" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>697</b></td></tr><tr><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>7</b> (Probe)</td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">00188654</td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/90944997" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">90944997</a></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">44968231</td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>H</b></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK56236/bin/ml167fu7.jpg" alt="Image ml167fu7.jpg" /></div></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK56236/bin/ml167fu8.jpg" alt="Image ml167fu8.jpg" /></div></td><td headers="hd_h_ml167.t2_1_1_1_2 hd_h_ml167.t2_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>136</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>1522</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>1648</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_11" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>>10000</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_12" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>>10000</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_13" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>4420</b></td></tr><tr><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>10</b></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">00012272</td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85239693" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85239693</a></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3234850</td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>H</b></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK56236/bin/ml167fu9.jpg" alt="Image ml167fu9.jpg" /></div></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK56236/bin/ml167fu10.jpg" alt="Image ml167fu10.jpg" /></div></td><td headers="hd_h_ml167.t2_1_1_1_2 hd_h_ml167.t2_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>249</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>915</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>714</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_11" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>>10000</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_12" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>1262</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_13" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>405</b></td></tr><tr><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>11</b></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">00188642</td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/90944985" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">90944985</a></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">44968219</td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>H</b></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
|
|
<div class="graphic"><img src="/books/NBK56236/bin/ml167fu11.jpg" alt="Image ml167fu11.jpg" /></div></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
|
|
<div class="graphic"><img src="/books/NBK56236/bin/ml167fu12.jpg" alt="Image ml167fu12.jpg" /></div></td><td headers="hd_h_ml167.t2_1_1_1_2 hd_h_ml167.t2_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>490</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>2820</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>5049</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_11" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>>10000</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_12" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>3388</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_13" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>2872</b></td></tr><tr><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>12</b></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">00188644</td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/90944987" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">90944987</a></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">44968221</td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>H</b></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
|
|
<div class="graphic"><img src="/books/NBK56236/bin/ml167fu13.jpg" alt="Image ml167fu13.jpg" /></div></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
|
|
<div class="graphic"><img src="/books/NBK56236/bin/ml167fu14.jpg" alt="Image ml167fu14.jpg" /></div></td><td headers="hd_h_ml167.t2_1_1_1_2 hd_h_ml167.t2_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>229</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>2083</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>6181</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_11" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>>10000</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_12" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>3629</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_13" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>7990</b></td></tr><tr><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>13</b></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">00188647</td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/90944990" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">90944990</a></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">44968224</td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>Me</b></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
|
|
<div class="graphic"><img src="/books/NBK56236/bin/ml167fu15.jpg" alt="Image ml167fu15.jpg" /></div></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
|
|
<div class="graphic"><img src="/books/NBK56236/bin/ml167fu16.jpg" alt="Image ml167fu16.jpg" /></div></td><td headers="hd_h_ml167.t2_1_1_1_2 hd_h_ml167.t2_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>269</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>899</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>1209</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_11" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>>10000</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_12" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>1136</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_13" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>304</b></td></tr><tr><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>14</b></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">00188648</td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/90944991" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">90944991</a></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">44968225</td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>Me</b></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
|
|
<div class="graphic"><img src="/books/NBK56236/bin/ml167fu17.jpg" alt="Image ml167fu17.jpg" /></div></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
|
|
<div class="graphic"><img src="/books/NBK56236/bin/ml167fu18.jpg" alt="Image ml167fu18.jpg" /></div></td><td headers="hd_h_ml167.t2_1_1_1_2 hd_h_ml167.t2_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>120</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>480</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>3331</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_11" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>>10000</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_12" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>922</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_13" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>4036</b></td></tr><tr><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>15</b></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">00188650</td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/90944993" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">90944993</a></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">44968227</td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>Me</b></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
|
|
<div class="graphic"><img src="/books/NBK56236/bin/ml167fu19.jpg" alt="Image ml167fu19.jpg" /></div></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
|
|
<div class="graphic"><img src="/books/NBK56236/bin/ml167fu20.jpg" alt="Image ml167fu20.jpg" /></div></td><td headers="hd_h_ml167.t2_1_1_1_2 hd_h_ml167.t2_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>239</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>916</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>7203</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_11" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>>10000</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_12" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>1501</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_13" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>3867</b></td></tr><tr><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>16</b></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">00188653</td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/90944996" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">90944996</a></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">44968230</td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>Me</b></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
|
|
<div class="graphic"><img src="/books/NBK56236/bin/ml167fu21.jpg" alt="Image ml167fu21.jpg" /></div></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
|
|
<div class="graphic"><img src="/books/NBK56236/bin/ml167fu22.jpg" alt="Image ml167fu22.jpg" /></div></td><td headers="hd_h_ml167.t2_1_1_1_2 hd_h_ml167.t2_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>81</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>206</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>889</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_11" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>>10000</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_12" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>557</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_13" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>352</b></td></tr><tr><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>17</b></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">00188673</td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/90945016" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">90945016</a></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">44968250</td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>H</b></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
|
|
<div class="graphic"><img src="/books/NBK56236/bin/ml167fu23.jpg" alt="Image ml167fu23.jpg" /></div></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
|
|
<div class="graphic"><img src="/books/NBK56236/bin/ml167fu24.jpg" alt="Image ml167fu24.jpg" /></div></td><td headers="hd_h_ml167.t2_1_1_1_2 hd_h_ml167.t2_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>254</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>1054</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>7280</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_11" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>>10000</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_12" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>1406</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_13" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>2401</b></td></tr><tr><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>18</b></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">00188681</td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/90945024" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">90945024</a></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">44968258</td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>H</b></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
|
|
<div class="graphic"><img src="/books/NBK56236/bin/ml167fu25.jpg" alt="Image ml167fu25.jpg" /></div></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
|
|
<div class="graphic"><img src="/books/NBK56236/bin/ml167fu26.jpg" alt="Image ml167fu26.jpg" /></div></td><td headers="hd_h_ml167.t2_1_1_1_2 hd_h_ml167.t2_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>790</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>6644</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>>10000</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_11" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>>10000</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_12" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>2706</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_13" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>5534</b></td></tr><tr><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>19</b></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">00188686</td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/90945029" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">90945029</a></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">44968263</td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>H</b></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
|
|
<div class="graphic"><img src="/books/NBK56236/bin/ml167fu27.jpg" alt="Image ml167fu27.jpg" /></div></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
|
|
<div class="graphic"><img src="/books/NBK56236/bin/ml167fu28.jpg" alt="Image ml167fu28.jpg" /></div></td><td headers="hd_h_ml167.t2_1_1_1_2 hd_h_ml167.t2_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>340</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>2379</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>3132</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_11" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>>10000</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_12" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>4820</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_13" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>1889</b></td></tr><tr><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>20</b></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">00185981</td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85239768" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85239768</a></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">44223970</td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>Me</b></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
|
|
<div class="graphic"><img src="/books/NBK56236/bin/ml167fu29.jpg" alt="Image ml167fu29.jpg" /></div></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
|
|
<div class="graphic"><img src="/books/NBK56236/bin/ml167fu30.jpg" alt="Image ml167fu30.jpg" /></div></td><td headers="hd_h_ml167.t2_1_1_1_2 hd_h_ml167.t2_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>11</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>20</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>186</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_11" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>1924</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_12" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>14</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_13" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>25</b></td></tr><tr><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>21</b></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">00188682</td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/90945025" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">90945025</a></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">44968259</td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>H</b></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
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|
<div class="graphic"><img src="/books/NBK56236/bin/ml167fu31.jpg" alt="Image ml167fu31.jpg" /></div></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
|
|
<div class="graphic"><img src="/books/NBK56236/bin/ml167fu32.jpg" alt="Image ml167fu32.jpg" /></div></td><td headers="hd_h_ml167.t2_1_1_1_2 hd_h_ml167.t2_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>813</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>6266</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>ND</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_11" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>ND</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_12" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>8307</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_13" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>>10000</b></td></tr><tr><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>22</b></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">00185963</td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85239750" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85239750</a></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">44223952</td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>H</b></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
|
|
<div class="graphic"><img src="/books/NBK56236/bin/ml167fu33.jpg" alt="Image ml167fu33.jpg" /></div></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
|
|
<div class="graphic"><img src="/books/NBK56236/bin/ml167fu34.jpg" alt="Image ml167fu34.jpg" /></div></td><td headers="hd_h_ml167.t2_1_1_1_2 hd_h_ml167.t2_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>40</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>96</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>1327</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_11" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>7448</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_12" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>206</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_13" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>1510</b></td></tr><tr><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>23</b></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">00229610</td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99380785" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">99380785</a></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">46916178</td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>H</b></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
|
|
<div class="graphic"><img src="/books/NBK56236/bin/ml167fu35.jpg" alt="Image ml167fu35.jpg" /></div></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
|
|
<div class="graphic"><img src="/books/NBK56236/bin/ml167fu36.jpg" alt="Image ml167fu36.jpg" /></div></td><td headers="hd_h_ml167.t2_1_1_1_2 hd_h_ml167.t2_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>29</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>90</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>1810</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_11" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>3294</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_12" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>30</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_13" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>458</b></td></tr><tr><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>24</b></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">00010428</td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85239685" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85239685</a></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3233012</td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>Me</b></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
|
|
<div class="graphic"><img src="/books/NBK56236/bin/ml167fu37.jpg" alt="Image ml167fu37.jpg" /></div></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
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|
<div class="graphic"><img src="/books/NBK56236/bin/ml167fu38.jpg" alt="Image ml167fu38.jpg" /></div></td><td headers="hd_h_ml167.t2_1_1_1_2 hd_h_ml167.t2_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>36</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>22</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>692</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_11" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>8744</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_12" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>98</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_13" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>452</b></td></tr><tr><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>25</b></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">00189310</td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99380783" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">99380783</a></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">46916176</td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>H</b></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK56236/bin/ml167fu39.jpg" alt="Image ml167fu39.jpg" /></div></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK56236/bin/ml167fu40.jpg" alt="Image ml167fu40.jpg" /></div></td><td headers="hd_h_ml167.t2_1_1_1_2 hd_h_ml167.t2_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>70</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>173</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>584</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_11" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>435</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_12" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>17</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_13" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>83</b></td></tr><tr><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>26</b></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">00185977</td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85239764" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85239764</a></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">44223966</td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>H</b></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK56236/bin/ml167fu41.jpg" alt="Image ml167fu41.jpg" /></div></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK56236/bin/ml167fu42.jpg" alt="Image ml167fu42.jpg" /></div></td><td headers="hd_h_ml167.t2_1_1_1_2 hd_h_ml167.t2_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>15</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>39</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>651</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_11" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>>10000</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_12" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>93</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_13" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>846</b></td></tr><tr><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>27</b></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">00229611</td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99380786" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">99380786</a></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">46916179</td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>H</b></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK56236/bin/ml167fu43.jpg" alt="Image ml167fu43.jpg" /></div></td><td headers="hd_h_ml167.t2_1_1_1_1 hd_h_ml167.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK56236/bin/ml167fu44.jpg" alt="Image ml167fu44.jpg" /></div></td><td headers="hd_h_ml167.t2_1_1_1_2 hd_h_ml167.t2_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>90</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>227</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>486</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_11" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>1320</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_12" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>76</b></td><td headers="hd_h_ml167.t2_1_1_1_3 hd_h_ml167.t2_1_1_2_13" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>313</b></td></tr></tbody></table></div></div></article><article data-type="fig" id="figobml167f6"><div id="ml167.f6" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK56236/bin/ml167f6.jpg" alt="Figure 6. A." /></div><h3><span class="label">Figure 6</span></h3><div class="caption"><p>A. Inhibitory dose response of <b>2</b> in the presence of three different ATP concentrations [1μM (filled circles), 50μM (empty circles), 100μM (empty squares)]. B. Inhibitory dose response of <b>2</b> in the presence of three different peptide concentrations [50μM (filled circles), 100μM (empty circles), 200μM (empty squares)].</p></div></div></article><article data-type="fig" id="figobml167f7"><div id="ml167.f7" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%207.%20Docking%20model%20of%202%20in%20the%20Clk1%20catalytic%20cleft.&p=BOOKS&id=56236_ml167f7.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK56236/bin/ml167f7.jpg" alt="Figure 7. Docking model of 2 in the Clk1 catalytic cleft." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 7</span><span class="title">Docking model of <b>2</b> in the Clk1 catalytic cleft</span></h3><div class="caption"><p>The binding pocket is depicted by molecular surface in mesh grey and the hydrogen bonds are labeled as green dotted lines. This figure was prepared with the program VIDA (OpenEye Scientific Software).</p></div></div></article><article data-type="table-wrap" id="figobml167tu3"><div id="ml167.tu3" class="table"><h3><span class="title">Properties computed from Structure</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK56236/table/ml167.tu3/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml167.tu3_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml167.tu3_1_1_1_1" rowspan="2" colspan="1" headers="hd_h_ml167.tu3_1_1_1_1" style="text-align:left;vertical-align:middle;">Calculated Property</th><th id="hd_h_ml167.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Probe Identity</th></tr><tr><th headers="hd_h_ml167.tu3_1_1_1_2" id="hd_h_ml167.tu3_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CID 44968231 (MLS002729079)</th></tr></thead><tbody><tr><td headers="hd_h_ml167.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Molecular Weight [g/mol]</td><td headers="hd_h_ml167.tu3_1_1_1_2 hd_h_ml167.tu3_1_1_2_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">335.35658</td></tr><tr><td headers="hd_h_ml167.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Molecular Formula</td><td headers="hd_h_ml167.tu3_1_1_1_2 hd_h_ml167.tu3_1_1_2_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">C19H17N3O3</td></tr><tr><td headers="hd_h_ml167.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">XLogP3-AA</td><td headers="hd_h_ml167.tu3_1_1_1_2 hd_h_ml167.tu3_1_1_2_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">2.7</td></tr><tr><td headers="hd_h_ml167.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H-Bond Donor</td><td headers="hd_h_ml167.tu3_1_1_1_2 hd_h_ml167.tu3_1_1_2_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">2</td></tr><tr><td headers="hd_h_ml167.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H-Bond Acceptor</td><td headers="hd_h_ml167.tu3_1_1_1_2 hd_h_ml167.tu3_1_1_2_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">6</td></tr><tr><td headers="hd_h_ml167.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Rotatable Bond Count</td><td headers="hd_h_ml167.tu3_1_1_1_2 hd_h_ml167.tu3_1_1_2_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">5</td></tr><tr><td headers="hd_h_ml167.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Tautomer Count</td><td headers="hd_h_ml167.tu3_1_1_1_2 hd_h_ml167.tu3_1_1_2_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">3</td></tr><tr><td headers="hd_h_ml167.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Exact Mass</td><td headers="hd_h_ml167.tu3_1_1_1_2 hd_h_ml167.tu3_1_1_2_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">335.126991</td></tr><tr><td headers="hd_h_ml167.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MonoIsotopic Mass</td><td headers="hd_h_ml167.tu3_1_1_1_2 hd_h_ml167.tu3_1_1_2_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">335.126991</td></tr><tr><td headers="hd_h_ml167.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Topological Polar Surface Area</td><td headers="hd_h_ml167.tu3_1_1_1_2 hd_h_ml167.tu3_1_1_2_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">84.3</td></tr><tr><td headers="hd_h_ml167.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Heavy Atom Count</td><td headers="hd_h_ml167.tu3_1_1_1_2 hd_h_ml167.tu3_1_1_2_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">25</td></tr><tr><td headers="hd_h_ml167.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Formal Charge</td><td headers="hd_h_ml167.tu3_1_1_1_2 hd_h_ml167.tu3_1_1_2_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml167.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Isotope Atom Count</td><td headers="hd_h_ml167.tu3_1_1_1_2 hd_h_ml167.tu3_1_1_2_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml167.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Defined Atom StereoCenter Count</td><td headers="hd_h_ml167.tu3_1_1_1_2 hd_h_ml167.tu3_1_1_2_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml167.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Undefined Atom StereoCenter Count</td><td headers="hd_h_ml167.tu3_1_1_1_2 hd_h_ml167.tu3_1_1_2_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml167.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Defined Bond StereoCenter Count</td><td headers="hd_h_ml167.tu3_1_1_1_2 hd_h_ml167.tu3_1_1_2_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml167.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Undefined Bond StereoCenter Count</td><td headers="hd_h_ml167.tu3_1_1_1_2 hd_h_ml167.tu3_1_1_2_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml167.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Covalently-Bonded Unit Count</td><td headers="hd_h_ml167.tu3_1_1_1_2 hd_h_ml167.tu3_1_1_2_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">1</td></tr><tr><td headers="hd_h_ml167.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Complexity</td><td headers="hd_h_ml167.tu3_1_1_1_2 hd_h_ml167.tu3_1_1_2_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">438</td></tr></tbody></table></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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