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<meta name="robots" content="INDEX,FOLLOW,NOARCHIVE" /><meta name="citation_inbook_title" content="Probe Reports from the NIH Molecular Libraries Program [Internet]" /><meta name="citation_title" content="A small molecule inhibitor of Caspase 1" /><meta name="citation_publisher" content="National Center for Biotechnology Information (US)" /><meta name="citation_date" content="2011/03/03" /><meta name="citation_author" content="Matthew B Boxer" /><meta name="citation_author" content="Min Shen" /><meta name="citation_author" content="Douglas S Auld" /><meta name="citation_author" content="James A Wells" /><meta name="citation_author" content="Craig J Thomas" /><meta name="citation_pmid" content="21735610" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK56241/" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="A small molecule inhibitor of Caspase 1" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="National Center for Biotechnology Information (US)" /><meta name="DC.Contributor" content="Matthew B Boxer" /><meta name="DC.Contributor" content="Min Shen" /><meta name="DC.Contributor" content="Douglas S Auld" /><meta name="DC.Contributor" content="James A Wells" /><meta name="DC.Contributor" content="Craig J Thomas" /><meta name="DC.Date" content="2011/03/03" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK56241/" /><meta name="description" content="A nitrile-containing propionic acid moiety as an electrophile for covalent attack by the active site cysteine residue of caspase 1 was investigated. Several cyanopropanate containing small molecules were synthesized, including one based upon the optimized peptidic scaffold of the prodrug VX-765. A number of these compounds were potent inhibitors of caspase 1 (IC50s ≤ 1 nM). Examination of these small molecules versus a caspase panel demonstrated an impressive degree of selectivity for caspase 1 inhibition. The small molecular probe ML132 (CID-4462093; NCGC-00183434) is the most potent caspase 1 inhibitor reported to date. It also possesses a unique selectivity pattern relative to other reported caspase inhibitors. 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<div class="pre-content"><div><div class="bk_prnt"><p class="small">NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.</p><p>Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010-. </p></div><div class="iconblock clearfix whole_rhythm no_top_margin bk_noprnt"><a class="img_link icnblk_img" title="Table of Contents Page" href="/books/n/mlprobe/"><img class="source-thumb" src="/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-mlprobe-lrg.png" alt="Cover of Probe Reports from the NIH Molecular Libraries Program" height="100px" width="80px" /></a><div class="icnblk_cntnt eight_col"><h2>Probe Reports from the NIH Molecular Libraries Program [Internet].</h2><a data-jig="ncbitoggler" href="#__NBK56241_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK56241_dtls__"><div>Bethesda (MD): National Center for Biotechnology Information (US); 2010-.</div></div><div class="half_rhythm"><ul class="inline_list"><li style="margin-right:1em"><a class="bk_cntns" href="/books/n/mlprobe/">Contents</a></li></ul></div><div class="bk_noprnt"><form method="get" action="/books/n/mlprobe/" id="bk_srch"><div class="bk_search"><label for="bk_term" class="offscreen_noflow">Search term</label><input type="text" title="Search this book" id="bk_term" name="term" value="" data-jig="ncbiclearbutton" /> <input type="submit" class="jig-ncbibutton" value="Search this book" submit="false" style="padding: 0.1em 0.4em;" /></div></form></div></div><div class="icnblk_cntnt two_col"><div class="pagination bk_noprnt"><a class="active page_link prev" href="/books/n/mlprobe/ml133/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/mlprobe/ml131/" title="Next page in this title">Next ></a></div></div></div></div></div>
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<div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><h1 id="_NBK56241_"><span class="title" itemprop="name">A small molecule inhibitor of Caspase 1</span></h1><p class="contrib-group"><span itemprop="author">Matthew B Boxer</span>, <span itemprop="author">Min Shen</span>, <span itemprop="author">Douglas S Auld</span>, <span itemprop="author">James A Wells</span>, and <span itemprop="author">Craig J Thomas</span>.</p><a data-jig="ncbitoggler" href="#__NBK56241_ai__" style="border:0;text-decoration:none">Author Information and Affiliations</a><div style="display:none" class="ui-widget" id="__NBK56241_ai__"><p class="contrib-group"><h4>Authors</h4><span itemprop="author">Matthew B Boxer</span>,<sup>a</sup> <span itemprop="author">Min Shen</span>,<sup>a</sup> <span itemprop="author">Douglas S Auld</span>,<sup>a</sup> <span itemprop="author">James A Wells</span>,<sup>b</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, National Institutes of Health, 9800 Medical Center Drive, MSC 3370 Bethesda, Maryland 20850</div><div class="affiliation"><sup>b</sup>
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Departments of Pharmaceutical Chemistry and Cellular and Molecular Pharmacology, University of California, San Francisco, Byers Hall, 1700 4th Street, San Francisco, CA 94158, USA</div></div><p class="small">Received: <span itemprop="datePublished">February 25, 2010</span>; Last Update: <span itemprop="dateModified">March 3, 2011</span>.</p></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="_abs_rndgid_" itemprop="description"><p>A nitrile-containing propionic acid moiety as an electrophile for covalent attack by the active site cysteine residue of caspase 1 was investigated. Several cyanopropanate containing small molecules were synthesized, including one based upon the optimized peptidic scaffold of the prodrug VX-765. A number of these compounds were potent inhibitors of caspase 1 (IC<sub>50</sub>s ≤ 1 nM). Examination of these small molecules versus a caspase panel demonstrated an impressive degree of selectivity for caspase 1 inhibition. The small molecular probe <a href="/pcsubstance/?term=ML132[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML132</a> (CID-4462093; NCGC-00183434) is the most potent caspase 1 inhibitor reported to date. It also possesses a unique selectivity pattern relative to other reported caspase inhibitors. A number of these compounds were assessed for their hydrolytic stability and selected absorption, distribution, metabolism and elimination (ADME) properties.</p></div><div class="h2"></div><p>Assigned Assay Grant #: X01 MH078950-01</p><p>Screening Center Name & PI: NIH Chemical Genomics Center & Dr. Christopher P. Austin</p><p>Chemistry Center Name & PI: NIH Chemical Genomics Center & Dr. Christopher P. Austin</p><p>Assay Submitter & Institution: Dr. Jim Wells, University of California at San Francisco</p><p>PubChem Summary Bioassay Identifier (AID): <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2389" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2389</a></p><div id="ml132.s1"><h2 id="_ml132_s1_">Probe Structure & Characteristics</h2><div id="ml132.fu1" class="figure bk_fig"><div class="graphic"><img src="/books/NBK56241/bin/ml132fu1.jpg" alt="ML132." /></div><h3><span class="title"><a href="/pcsubstance/?term=ML132[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML132</a></span></h3></div><div id="ml132.tu1" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK56241/table/ml132.tu1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml132.tu1_lrgtbl__"><table><thead><tr><th id="hd_h_ml132.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CID/ML#</th><th id="hd_h_ml132.tu1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Target Name</th><th id="hd_h_ml132.tu1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">IC<sub>5</sub>0/EC<sub>50</sub> (nM) [SID, AID]</th><th id="hd_h_ml132.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_ml132.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_ml132.tu1_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Fold Selective</th><th id="hd_h_ml132.tu1_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Secondary Assay(s)<br />Name: IC<sub>50</sub>/EC<sub>50</sub> (nM) [SID, AID]</th></tr></thead><tbody><tr><td headers="hd_h_ml132.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">44620939/<a href="/pcsubstance/?term=ML132[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML132</a></td><td headers="hd_h_ml132.tu1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Caspase 1</td><td headers="hd_h_ml132.tu1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.023nM [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/87544173" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">87544173</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2389" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2389</a>]</td><td headers="hd_h_ml132.tu1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Panel of 9 Caspases</td><td headers="hd_h_ml132.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/87544173" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">87544173</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2389" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2389</a>]</td><td headers="hd_h_ml132.tu1_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">> 1000-fold</td><td headers="hd_h_ml132.tu1_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Protease panel [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/87544173" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">87544173</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2389" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2389</a>]</td></tr></tbody></table></div></div></div><div id="ml132.s2"><h2 id="_ml132_s2_">Recommendations for scientific use of the probe</h2><p>Caspase 1, also known as interleukin-converting enzyme or ICE, is responsible for the proteolytic activation of interleukin (IL)-1β and IL-18. [<a class="bk_pop" href="#ml132.r1">1</a>] IL-1β and IL-18 are cytokines that play a major role in the immune response and within numerous autoimmune and inflammatory diseases. Caspase 1 is constitutively and inducibly expressed in immune response elements such as T cells, macrophages and neutrophils. Inhibitors of caspase 1 are sought for intervention strategies within ischemic disorders, Huntington’s disease, amyotrophic lateral sclerosis (ALS), rheumatoid arthritis, osteoarthritis, inflammatory bowel disease and sepsis.</p></div><div id="ml132.s3"><h2 id="_ml132_s3_">1. Introduction</h2><p>Caspases are cysteine proteases with a strict specificity for cleaving peptide sequences C-terminal to aspartic acids residues. Currently, 12 caspase isozymes have been identified in humans, with numerous reported activities. Caspases are often subcategorized as either pro-apoptotic or pro-inflammatory enzymes. A prominent member of the pro-inflammatory class is caspase 1, also known as interleukin-converting enzyme or ICE, which is responsible for the proteolytic activation of interleukin (IL)-1β and IL-18 [<a class="bk_pop" href="#ml132.r1">1</a>]. IL-1β and IL-18 are cytokines that play a major role in the immune response and within numerous autoimmune and inflammatory diseases [<a class="bk_pop" href="#ml132.r2">2</a>]. Caspase 1 is constitutively and inducibly expressed in immune response elements such as T cells, macrophages and neutrophils. Procaspase 1 is known to associate with several multi-protein complexes capable of responding to numerous external stimuli, suggesting that caspase 1 is a major regulator of the inflammation response. Targeting proteases, and specifically caspases, via small molecule therapeutics is an active area of research. Small molecule inhibitors of selected proteases have entered the clinic, and many have received approval. Inhibitors of caspase 1 are sought for intervention strategies within ischemic disorders, Huntington’s disease, amyotrophic lateral sclerosis (ALS), rheumatoid arthritis, osteoarthritis, inflammatory bowel disease and sepsis.</p><p>The overall goal of this project is to screen for and/or design inhibitors of caspase 1 that are potent and selective over the 11 additional caspase isozymes. To date, at least three caspase 1 inhibitors have entered clinical evaluation, including Pralnacasan (VX-740), IDN-6556 and VX-765. All three agents are active site inhibitors that act through reversible (Pralnacasan and VX-765) or irreversible (IDN-6556) covalent modification of the catalytic cysteine residue. These agents have impressive potency versus caspase 1 (for instance, VX-740 has a published Ki of 1 nM) and good reported selectivity [<a class="bk_pop" href="#ml132.r3">3</a>]. Any probe from this project must be an improvement on current art (i.e. potency better than VX-765 and equal selectivity). These agents, and the probes found herein, are covalent modifiers of their target. Often, covalent modifiers are avoided due to promiscuity issues and potential for toxicities within <i>in vivo</i> studies. However, a large number of known drugs do indeed inhibit their target via covalent modification at the orthosteric site, and as tool compounds, covalent modifiers can be very useful if their selectivity can be shown versus related targets.</p></div><div id="ml132.s4"><h2 id="_ml132_s4_">2. Materials and Methods</h2><div id="ml132.s5"><h3>General Methods for Chemistry</h3><p>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 × 75 mm) 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 (220 nM). 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 × 75 mm) 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 × 100 mm) 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><div id="ml132.s6"><h3>2.1. Assays</h3><p>The biochemical assay was configured using purified caspase 1 at a high enzyme concentration to promote formation of the homodimers, and thus facilitate the identification of allosteric inhibitors. The overall goal was to identify reversible inhibitors with better drug-like properties than the currently available set of aspartyl-containing peptidomimetics that covalently bind the active site. Caspase 1 was assayed using the profluorescent substrate Ac-WEHD-AFC. After initiation of the assay with substrate, the plates were rapidly read using an automated robotic system (Kalypsys, Inc.) to maintain consistent timing. A kinetic mode of detection was used where the initial rate was collected (estimated final product formation was ~10%). Compounds were screened as a concentration-titration series that ranged from 57μM to 3.7nM. Below is the protocol used for caspase 1.</p><p>Caspase 1 was prepared in buffer (50mM HEPES pH 7.5, 50mM KCl, 200mM NaCl, 10mM DTT, 0.1% CHAPS) at a concentration of 66.6nM, and 3μl was dispensed to all wells using black solid Kalypsys 1536-well plates. 20nl of DMSO containing compounds was added using a Kalypsys pin-tool to columns 5–48. Then, 20nl of DMSO solution from a control plate was added to columns 1–4. Controls were: Column 1, 16 point titration with each concentration in duplicate (1:1 dilutions in DMSO; final starting concentration was 57μM) of the caspase 1 inhibitor Ac-WEHD-CHO (Alexis Biochemicals); Column 2, a 16 point titration with each concentration in duplicate of the free AFC fluorophore prepared in DMSO (Alexis Biochemicals), final starting concentration was 40μM; Column 3 neutral (DMSO only) control; Column 4: DMSO alone, to serve as a negative control (no substrate was added). Then 1μl of 20μM of the substrate Ac-WEHD-AFC (Alexis Biochemicals) prepared in the same buffer was dispensed to all wells except columns 2 and 4, and the plates were immediately transferred (<1 min) to the Viewlux. The plates were then exposed using 405 nm excitation/520 nm emission filters for 4 sec and read at 20 sec intervals for 3 min. Final enzyme concentration was 50 nM and the final substrate concentration was 5μM.</p><p>Concentration-response curves were fitted to the data calculated from slope of the linear regression of fluorescent intensity versus time (the rate). The concentration-effect curves were then classified based on curve quality (r<sup>2</sup>), response magnitude and degree of measured activity. Active compounds showed concentration-dependent decreases in the measured rate. Inconclusive compounds had appreciable concentration-dependent effects on both the measured rate and the interpolated basal fluorescence intensity at the start of the reaction, but where the basal fluorescent intensity was marginal (e.g. < 10-fold). Inconclusive compounds also encompass highly fluorescent compounds (> 100-fold increases in fluorescent intensities values relative to controls) where artificial concentration-dependent decreases in the rate occurred at high compound concentrations due to fluorescent interferences.</p><p>The assay was well behaved; the signal-to-background ratio was on average 13 and the average Z′ screening factor associated with each plate was 0.8, indicating a robust performance of the screen. A total of 20 actives were found and submitted. None of these agents had the requirements to satisfy the probe definition. Additional assays were performed by commercial vendor (<a href="http://www.reactionbiology.com" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.reactionbiology.com</a>); these assays rely upon a peptide cleavage assay of a caged florophore (Z-LEHD)<sub>2</sub>-R110 tetrapeptide.</p></div><div id="ml132.s7"><h3>2.2. Probe Chemical Characterization</h3><div id="ml132.f5" class="figure bk_fig"><div class="graphic"><img src="/books/NBK56241/bin/ml132f5.jpg" alt="Scheme 1. Conditions and reagents." /></div><h3><span class="label">Scheme 1</span><span class="title">Conditions and reagents</span></h3><div class="caption"><p>(a) EDC, DMAP, CH<sub>2</sub>Cl<sub>2</sub>, 6 h(59%); (b) TFAA, DIPEA, CH<sub>2</sub>Cl<sub>2</sub>, 0°C, 30 min. (90%); (c) thionyl chloride (excess), EtOH, 0°C (95%); (d) TFAA, DIPEA, CH<sub>2</sub>Cl<sub>2</sub>, 0°C, 30 min. (86%); (e) NMM, DME, then NH<sub>4</sub>OH (73%); (f) TMSN<sub>3</sub>, Bu<sub>2</sub>SnO (0.6 equiv.), toluene, μW, 100°C, 1 h (77%); (g) TFAA, DIPEA, CH<sub>2</sub>Cl<sub>2</sub>, 0°C, 30 min. (80%).</p></div></div><div id="ml132.f6" class="figure bk_fig"><div class="graphic"><img src="/books/NBK56241/bin/ml132f6.jpg" alt="Scheme 2. Conditions and reagents." /></div><h3><span class="label">Scheme 2</span><span class="title">Conditions and reagents</span></h3><div class="caption"><p>(a) EDC, HOBt, DMF, rt, 8 h; (b) DBU, CH<sub>2</sub>Cl<sub>2</sub>, rt (71% over 2 steps); (c) HATU, DIPEA, DMF, rt, 2 h; (d)TFA,CH<sub>2</sub>Cl<sub>2</sub> (1:1), rt, 4 h (85% over 2 steps); (e) DBU, DMF, 5 min. then <b>15</b>, HATU, DIPEA, DMF, 0 °C, 2h; (f) TBAF, THF, 0 °C (72% over 2 steps); (g) DBU, DMF, 5 min. then <b>15</b>, HATU, DIPEA, DMF, 0 °C, 2h (91%); (h) DBU, DMF, 5 min. then <b>15</b>, HATU, DIPEA, DMF, 0 °C, 2h (82%).</p></div></div><p>NCGC-00183434/CID-44620939/<a href="/pcsubstance/?term=ML132[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML132</a>: <sup>1</sup>H NMR (400 MHz, DMSO-<i>d</i><sub>6</sub>) δ ppm 8.68 (d, <i>J</i>=7.4 Hz, 1 H), 7.79 (d, <i>J</i>=1.9 Hz, 1 H), 7.64 (d, <i>J</i>=9.0 Hz, 1 H), 7.56 (dd, <i>J</i>=8.6, 1.9 Hz, 1 H), 6.73 (d, <i>J</i>=8.6 Hz, 1 H), 5.95 (b, 2H), 4.83 (q, <i>J</i>=7.4 Hz, 1H), 4.64 (d, <i>J</i>=9.0 Hz, 1 H), 4.20 – 4.30 (dd, <i>J</i>= 8.2, 5.6 Hz 1 H), 3.69 – 3.80 (m, 1 H), 3.60 (m, 1 H), 2.79 (dd, <i>J</i>=6.7, 3.1 Hz, 2 H), 1.99 – 2.11 (m, 1 H), 1.63 – 1.96 (m, 4 H), 0.99 (s, 9 H) <sup>13</sup>C NMR (100 MHz, DMSO-<i>d</i><i><sub>6</sub></i>): 172.2, 170.6, 169.9, 165.8, 148.0, 129.4, 128.2, 122.1, 119.1, 116.4, 114.4, 59.7, 57.8, 48.2, 37.4, 36.6, 35.3, 29.5, 27.0, 25.1. LC/MS: Method 1, retention time: 4.595 min; Method 2, retention time: 3.591 min; HRMS: <i>m/z</i> (M+H<sup>+</sup>) = 477.1784 (Calculated for C<sub>22</sub>H<sub>28</sub>N<sub>5</sub>O<sub>5</sub>Cl = 477.1779). [α]<sup>22</sup><sub>D</sub> = −65 (<i>c</i> 1.0, MeOH). Solubility (PBS, pH 7.4, 23°C) ≥ 100μM. Stability profile over 100 hrs (water, pH 7, pH 2 and pH 8, 23°C) is shown in <a class="figpopup" href="/books/NBK56241/figure/ml132.f1/?report=objectonly" target="object" rid-figpopup="figml132f1" rid-ob="figobml132f1">Figure 1</a>.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml132f1" co-legend-rid="figlgndml132f1"><a href="/books/NBK56241/figure/ml132.f1/?report=objectonly" target="object" title="Figure 1" class="img_link icnblk_img figpopup" rid-figpopup="figml132f1" rid-ob="figobml132f1"><img class="small-thumb" src="/books/NBK56241/bin/ml132f1.gif" src-large="/books/NBK56241/bin/ml132f1.jpg" alt="Figure 1. Aqueous stability of prodrugs VX-765 (1)(♦) and NCGC-00185682 (3)(X) and drugs VRT-043198 (2b)(▴), NCGC-00183434/CID-44620939/ML132 (4)(■) and NCGC-00183681 (16)(●) at neutral (pH 7 - black), acidic (pH 2 - red), and basic (pH 8 - blue) conditions." /></a><div class="icnblk_cntnt" id="figlgndml132f1"><h4 id="ml132.f1"><a href="/books/NBK56241/figure/ml132.f1/?report=objectonly" target="object" rid-ob="figobml132f1">Figure 1</a></h4><p class="float-caption no_bottom_margin">Aqueous stability of prodrugs VX-765 (<i>1</i>)(♦) and NCGC-00185682 (<i>3</i>)(X) and drugs VRT-043198 (<i>2b</i>)(▴), NCGC-00183434/CID-44620939/ML132 (<i>4</i>)(■) and NCGC-00183681 (<i>16</i>)(●) at neutral (pH 7 - black), acidic (pH 2 - red), and basic <a href="/books/NBK56241/figure/ml132.f1/?report=objectonly" target="object" rid-ob="figobml132f1">(more...)</a></p></div></div></div><div id="ml132.s8"><h3>2.3. Probe Preparation</h3><p>Appropriately substituted ethyl-3-cyanopropanoate derivatives are not commercially available, and therefore required synthetic elaboration. As we desired to explore both an active and prodrug form of our conceived molecule, we examined alternative protecting group strategies for the acid side chain (<a class="figpopup" href="/books/NBK56241/figure/ml132.f5/?report=objectonly" target="object" rid-figpopup="figml132f5" rid-ob="figobml132f5">Scheme 1</a>). Commercially available Fmoc protected D-isoasparagine (<b>5</b>) offered a convenient entry point to both required building blocks. Treatment of <b>5</b> with 2-(trimethylsilyl)ethanol, EDC and DMAP in methylene chloride provided the TMSE protected <b>6</b> in good yield. Conversion of <b>6</b> to nitrile <b>7</b> was accomplished by treatment with trifluoroacetic anhydride and Hunig’s base. A similar sequence was used to produce the ethyl ester <b>9</b>. In addition to the ester prodrug and the active cyanopropionic acid, it was of interest to explore carboxylic acid mimetics. As such, we undertook the synthesis of a tetrazole version of the key ethyl-3-cyanopropanoate moiety. Here, we utilized the previously reported Fmoc protected (S)-2-amino-3-cyanopropanoic acid (<b>10</b>). Conversion to amide <b>11</b> was required prior to formation of the tetrazole <b>12</b>. The amide was formed via the mixed anhydride, followed by treatment with ammonium hydroxide. Tetrazole formation was accomplished via microwave irradiation of the nitrile <b>11</b> and TMS-azide in the presence of dibutylstannanone. Dehydration to nitrile <b>13</b> was accomplished in a manner analogous to <b>7</b> and <b>9</b>. With appropriately substituted/protected cyanopropanoate building blocks, we next turned our attention to the trimer core of VX-765 (<a class="figpopup" href="/books/NBK56241/figure/ml132.f6/?report=objectonly" target="object" rid-figpopup="figml132f6" rid-ob="figobml132f6">Scheme 2</a>). Both Fmoc protected L-<i>tert</i>-leucine and <i>tert</i>-butyl-L-prolinate are commercially available and were easily coupled via treatment with EDC and HOBt. Fmoc removal was effected by treatment with DBU resulting in the protected dimer <b>14</b>. Coupling of <b>14</b> with 4-amino-3-chlorobenzoic acid was accomplished using HATU and Hunig’s base in DMF. TFA mediated removal of the <i>tert</i>-butyl group yielded the carboxylic acid <b>15</b>. A single pot deprotection-coupling sequence was used to generate the desired final products. Treatment of <b>7</b>, <b>9</b> and <b>13</b> with DBU in DMF effected deprotection to the free amines which were added sequentially to <b>15,</b> Hunig’s base and finally HATU to yield the coupled products. The generation of <b>4</b> (NCGC-00183434/CID-44620939/<a href="/pcsubstance/?term=ML132[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML132</a>) further required TBAF mediated removal of the TMSE group.</p></div></div><div id="ml132.s9"><h2 id="_ml132_s9_">3. Results</h2><p>Please see subsection for a detailed description of the results.</p><div id="ml132.s10"><h3>3.1. Summary of Screening Results</h3><p>Not applicable (these agents were rationally designed following our inability to discover new agents within the qHTS Assay for Allosteric/Competitive Inhibitors of Caspase-1; AID <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/900" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">900</a>).</p><div id="ml132.s11"><h4>Identification of lead</h4><p>The design of small molecule inhibitors of cysteine proteases relies heavily on covalent modification of the active site cysteine through reaction with the highly nucleophilic thiolate. Electrophilic ‘warhead’ moieties suitable for this modification include the aforementioned aldehyde, Michael acceptors (for instance, vinyl sulfones), α-halo ketones, epoxides and nitriles. In particular, nitrile-based cysteine protease inhibitors have found utility versus cathepsin K [<a class="bk_pop" href="#ml132.r4">4</a>], TbCatB [<a class="bk_pop" href="#ml132.r5">5</a>] and cruzain [<a class="bk_pop" href="#ml132.r6">6</a>]. We endeavored to explore the promise of cyanopropanoates as caspase inhibitors (<a class="figpopup" href="/books/NBK56241/figure/ml132.f1/?report=objectonly" target="object" rid-figpopup="figml132f1" rid-ob="figobml132f1">Figure 1B</a>). To explore the potential of this functional moiety, we took advantage of the peptidic scaffold of VX-765. Further, we incorporated the ethyl-3- cyanopropanoate to mimic the prodrug qualities associated with VX-765 (<a class="figpopup" href="/books/NBK56241/figure/ml132.f1/?report=objectonly" target="object" rid-figpopup="figml132f1" rid-ob="figobml132f1">Figure 1</a>). VX-765 (<b>1</b>) is a prodrug that requires esterase cleavage of the 5-ethoxydihydrofuran-2(3H)-one moiety to yield the aldehyde functionality of the drug VRT-043198 (<b>2b</b>) (CID-11443029), which acts as a potent electrophile for attack by the active site cysteine thiol (<a class="figpopup" href="/books/NBK56241/figure/ml132.f1/?report=objectonly" target="object" rid-figpopup="figml132f1" rid-ob="figobml132f1">Figure 1A</a>). The remainder of the VX-765 (<b>1</b>) molecule establishes key binding contacts with caspase 1 that enhance the potency of the interaction and confer a modest degree of selectivity.</p><div id="ml132.tu2" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK56241/table/ml132.tu2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml132.tu2_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">Probe</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">NCGC-00183434</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">MLS003178557</td></tr><tr><td rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">Analog</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">NCGC-00241069</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">MLS003178558</td></tr><tr><td rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">Analog</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">NCGC-00241070</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">MLS003178559</td></tr><tr><td rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">Analog</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">NCGC-00241071</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">MLS003178560</td></tr><tr><td rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">Analog</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">NCGC-00185682</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">MLS003178561</td></tr><tr><td rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">Analog</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">NCGC-00241073</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">MLS003178562</td></tr></tbody></table></div></div><div id="ml132.f2" class="figure bk_fig"><div class="graphic"><img src="/books/NBK56241/bin/ml132f2.jpg" alt="Figure 2. A." /></div><h3><span class="label">Figure 2</span></h3><div class="caption"><p><b>A.</b> The structure of VX-765 (<b>1</b>) and schematic representation of esterase cleavage of the 5-ethoxydihydrofuran-2(3H)-one moiety to yield the active drug VRT-043198 (<b>2b</b>). <b>B.</b> The structure of NCGC-00185682 (<b>3</b>) and putative esterase cleavage of the ethyl-3-cyanopropanoate moiety to yield active agent NCGC-00183434/CID-44620939 (<b>4</b>).</p></div></div></div></div><div id="ml132.s12"><h3>3.2. Dose Response Curves for Probe</h3><div id="ml132.f3" class="figure bk_fig"><div class="graphic"><img src="/books/NBK56241/bin/ml132f3.jpg" alt="Figure 3. Structure of NCGC-00183434/CID-44620939/ML132 and dose response curve for data acquired from the fluorescent enzyme assay using YVAD-CHO as a control and YVAD-AMC as the substrate." /></div><h3><span class="label">Figure 3</span><span class="title">Structure of NCGC-00183434/CID-44620939/<a href="/pcsubstance/?term=ML132[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML132</a> and dose response curve for data acquired from the fluorescent enzyme assay using YVAD-CHO as a control and YVAD-AMC as the substrate</span></h3></div></div><div id="ml132.s13"><h3>3.3. Scaffold/Moiety Chemical Liabilities</h3><p>NCGC-00183434/CID-44620939/<a href="/pcsubstance/?term=ML132[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML132</a> contains nitrile and acid moieties. The nitrile group is intended to be a covalent modifier of the target caspase 1. Often, covalent modifiers are avoided due to promiscuity issues and potential for toxicities within <i>in vivo</i> studies. However, a large number of known drugs do indeed inhibit their target via covalent modification at the orthosteric site, and as tool compounds, covalent modifiers can be very useful if their selectivity can be shown versus related targets. We have profiled these agents for selectivity versus within a commercial panel of caspases offered by Reaction Biology Corporation. This data confirmed the potent inhibitory capacity of <b>2b</b> versus caspase 1 (IC<sub>50</sub> = 0.204nM); however, the IC<sub>50</sub> values found versus caspase 4 (IC<sub>50</sub> = 14.5nM) and caspase 8 (IC<sub>50</sub> = 3. nM) differed slightly from the reported <i>K</i>i values. The results against caspase 6 (IC<sub>50</sub> ≥ 10,000nM) and caspase 9 (IC<sub>50</sub> = 5.07nM) were significantly different from those reported by Randle and coworkers [<a class="bk_pop" href="#ml132.r7">7</a>]. The Reaction Biology Corporation panel also included caspase 5 (IC<sub>50</sub> = 10.6nM), caspase 10 (IC<sub>50</sub> = 66.5nM) and caspase 14 (IC<sub>50</sub> = 58.5nM), and the data presented here represents the first disclosure of the IC<sub>50</sub> values for <b>2b</b> versus these targets. The results for <b>4</b> demonstrated an impressive potency against caspase 1 (IC<sub>50</sub> = 0.023nM) and a similar selectivity profile as <b>2b</b>. The only prominent divergence between the selectivity profiles of <b>4</b> and <b>2b</b> was a sharp drop in the ability to inhibit caspase 14 (IC<sub>50</sub> = 801nM and IC<sub>50</sub> = 58.5nM, respectively). The caspase 1 inhibition data generated in this panel for <b>3</b> and <b>16</b> was similar to the data generated in our caspase 1 assay, with reported IC<sub>50</sub> values of 43.4 nM and 2.58 nM, respectively. A particularly interesting aspect of these molecules was the high selectivity for caspase 1. NCGC-00183681 (<b>16</b>) registered an IC<sub>50</sub> value of 91.5nM versus caspase 9. All other activities were above the 1μM threshold. In addition to the primary molecules of this study, we were interested in establishing cyanopropanoates as general caspase directing ‘warheads’ for future utility in the search for other potent and selective small molecule inhibitors of caspases. As such, we included the general nitrile-Asp directing group into the common peptide caspase inhibitors YVAD. The resulting agent, YVAD-CN (<b>20</b>), was profiled, and the results clearly demonstrate that cyanopropanoates represent a general moiety for reversible, covalent modification of caspases. Based upon this data, we conclude that these agents do not represent promiscuous covalent protein modifiers.</p><p>The acid moiety can cause issues with membrane permeability (though not always). In order to combat this, we have provided a pro-drug version of NCGC-00183434/CID-44620939.</p></div><div id="ml132.s14"><h3>3.4. SAR Tables</h3><div id="ml132.t1" class="table"><h3><span class="label">Table 1</span><span class="title">Investigation of SAR around aryl ring</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK56241/table/ml132.t1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml132.t1_lrgtbl__"><table class="no_margin"><thead><tr><th id="hd_h_ml132.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;"></th><th id="hd_h_ml132.t1_1_1_1_2" colspan="5" rowspan="1" style="text-align:center;vertical-align:bottom;">
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<div class="graphic"><img src="/books/NBK56241/bin/ml132fu3.jpg" alt="Image ml132fu3.jpg" /></div></th></tr><tr><th headers="hd_h_ml132.t1_1_1_1_1 hd_h_ml132.t1_1_1_1_2" id="hd_h_ml132.t1_1_1_2_1" colspan="6" rowspan="1" style="text-align:center;vertical-align:bottom;">
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<span class="hr"></span></th></tr><tr><th headers="hd_h_ml132.t1_1_1_1_1 hd_h_ml132.t1_1_1_2_1" id="hd_h_ml132.t1_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">Entry</th><th headers="hd_h_ml132.t1_1_1_1_2 hd_h_ml132.t1_1_1_2_1" id="hd_h_ml132.t1_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">Ar</th><th headers="hd_h_ml132.t1_1_1_1_2 hd_h_ml132.t1_1_1_2_1" id="hd_h_ml132.t1_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">Internal ID<sup><a class="bk_pop" href="#ml132.tfn1">a</a></sup></th><th headers="hd_h_ml132.t1_1_1_1_2 hd_h_ml132.t1_1_1_2_1" id="hd_h_ml132.t1_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">CID</th><th headers="hd_h_ml132.t1_1_1_1_2 hd_h_ml132.t1_1_1_2_1" id="hd_h_ml132.t1_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">SID</th><th headers="hd_h_ml132.t1_1_1_1_2 hd_h_ml132.t1_1_1_2_1" id="hd_h_ml132.t1_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">IC50 (nM)<sup><a class="bk_pop" href="#ml132.tfn2">b</a></sup></th></tr></thead><tbody><tr><td headers="hd_h_ml132.t1_1_1_1_1 hd_h_ml132.t1_1_1_2_1 hd_h_ml132.t1_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml132.t1_1_1_1_2 hd_h_ml132.t1_1_1_2_1 hd_h_ml132.t1_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK56241/bin/ml132fu4.jpg" alt="Image ml132fu4.jpg" /></div></td><td headers="hd_h_ml132.t1_1_1_1_2 hd_h_ml132.t1_1_1_2_1 hd_h_ml132.t1_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NCGC-00183434</td><td headers="hd_h_ml132.t1_1_1_1_2 hd_h_ml132.t1_1_1_2_1 hd_h_ml132.t1_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">44620939</td><td headers="hd_h_ml132.t1_1_1_1_2 hd_h_ml132.t1_1_1_2_1 hd_h_ml132.t1_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/87544173" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">87544173</a></td><td headers="hd_h_ml132.t1_1_1_1_2 hd_h_ml132.t1_1_1_2_1 hd_h_ml132.t1_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.47</td></tr><tr><td headers="hd_h_ml132.t1_1_1_1_1 hd_h_ml132.t1_1_1_2_1 hd_h_ml132.t1_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml132.t1_1_1_1_2 hd_h_ml132.t1_1_1_2_1 hd_h_ml132.t1_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK56241/bin/ml132fu5.jpg" alt="Image ml132fu5.jpg" /></div></td><td headers="hd_h_ml132.t1_1_1_1_2 hd_h_ml132.t1_1_1_2_1 hd_h_ml132.t1_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NCGC-00241070</td><td headers="hd_h_ml132.t1_1_1_1_2 hd_h_ml132.t1_1_1_2_1 hd_h_ml132.t1_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">46916205</td><td headers="hd_h_ml132.t1_1_1_1_2 hd_h_ml132.t1_1_1_2_1 hd_h_ml132.t1_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99380812" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">99380812</a></td><td headers="hd_h_ml132.t1_1_1_1_2 hd_h_ml132.t1_1_1_2_1 hd_h_ml132.t1_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.424</td></tr><tr><td headers="hd_h_ml132.t1_1_1_1_1 hd_h_ml132.t1_1_1_2_1 hd_h_ml132.t1_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml132.t1_1_1_1_2 hd_h_ml132.t1_1_1_2_1 hd_h_ml132.t1_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK56241/bin/ml132fu6.jpg" alt="Image ml132fu6.jpg" /></div></td><td headers="hd_h_ml132.t1_1_1_1_2 hd_h_ml132.t1_1_1_2_1 hd_h_ml132.t1_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NCGC-00241069</td><td headers="hd_h_ml132.t1_1_1_1_2 hd_h_ml132.t1_1_1_2_1 hd_h_ml132.t1_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">46916204</td><td headers="hd_h_ml132.t1_1_1_1_2 hd_h_ml132.t1_1_1_2_1 hd_h_ml132.t1_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99380811" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">99380811</a></td><td headers="hd_h_ml132.t1_1_1_1_2 hd_h_ml132.t1_1_1_2_1 hd_h_ml132.t1_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2.09</td></tr><tr><td headers="hd_h_ml132.t1_1_1_1_1 hd_h_ml132.t1_1_1_2_1 hd_h_ml132.t1_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml132.t1_1_1_1_2 hd_h_ml132.t1_1_1_2_1 hd_h_ml132.t1_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK56241/bin/ml132fu7.jpg" alt="Image ml132fu7.jpg" /></div></td><td headers="hd_h_ml132.t1_1_1_1_2 hd_h_ml132.t1_1_1_2_1 hd_h_ml132.t1_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NCGC-00241073</td><td headers="hd_h_ml132.t1_1_1_1_2 hd_h_ml132.t1_1_1_2_1 hd_h_ml132.t1_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">46916207</td><td headers="hd_h_ml132.t1_1_1_1_2 hd_h_ml132.t1_1_1_2_1 hd_h_ml132.t1_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99380814" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">99380814</a></td><td headers="hd_h_ml132.t1_1_1_1_2 hd_h_ml132.t1_1_1_2_1 hd_h_ml132.t1_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.44</td></tr><tr><td headers="hd_h_ml132.t1_1_1_1_1 hd_h_ml132.t1_1_1_2_1 hd_h_ml132.t1_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5</td><td headers="hd_h_ml132.t1_1_1_1_2 hd_h_ml132.t1_1_1_2_1 hd_h_ml132.t1_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK56241/bin/ml132fu8.jpg" alt="Image ml132fu8.jpg" /></div></td><td headers="hd_h_ml132.t1_1_1_1_2 hd_h_ml132.t1_1_1_2_1 hd_h_ml132.t1_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NCGC-00241071</td><td headers="hd_h_ml132.t1_1_1_1_2 hd_h_ml132.t1_1_1_2_1 hd_h_ml132.t1_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">46916206</td><td headers="hd_h_ml132.t1_1_1_1_2 hd_h_ml132.t1_1_1_2_1 hd_h_ml132.t1_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99380813" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">99380813</a></td><td headers="hd_h_ml132.t1_1_1_1_2 hd_h_ml132.t1_1_1_2_1 hd_h_ml132.t1_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5.36</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>a</dt><dd><div id="ml132.tfn1"><p class="no_margin">All compounds synthesized at NCGC</p></div></dd><dt>b</dt><dd><div id="ml132.tfn2"><p class="no_margin">IC50 values were determined at NCGC utilizing a fluorescent enzyme assay using the appropriate AFC-labeled peptide.</p></div></dd></dl></div></div></div><div id="ml132.t2" class="table"><h3><span class="label">Table 2</span><span class="title">IC<sub>50</sub> values for selected compounds versus caspase panel</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK56241/table/ml132.t2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml132.t2_lrgtbl__"><table class="no_margin"><thead><tr><th id="hd_h_ml132.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;"><i>Compound</i></th><th id="hd_h_ml132.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;"><i>Caspase 1 (nM)</i></th><th id="hd_h_ml132.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;"><i>Caspase 3 (nM)</i></th><th id="hd_h_ml132.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;"><i>Caspase 4 (nM)</i></th><th id="hd_h_ml132.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;"><i>Caspase 5 (nM)</i></th><th id="hd_h_ml132.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;"><i>Caspase 6 (nM)</i></th><th id="hd_h_ml132.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;"><i>Caspase 7 (nM)</i></th><th id="hd_h_ml132.t2_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;"><i>Caspase 8 (nM)</i></th><th id="hd_h_ml132.t2_1_1_1_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;"><i>Caspase 9 (nM)</i></th><th id="hd_h_ml132.t2_1_1_1_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;"><i>Caspase 10 (nM)</i></th><th id="hd_h_ml132.t2_1_1_1_11" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;"><i>Caspase 14 (nM)</i></th></tr></thead><tbody><tr><td headers="hd_h_ml132.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">VRT-043198(<b>2b</b>) (Drug)</td><td headers="hd_h_ml132.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>0.204</b></td><td headers="hd_h_ml132.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>>10000</b></td><td headers="hd_h_ml132.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>14.5</b></td><td headers="hd_h_ml132.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>10.6</b></td><td headers="hd_h_ml132.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>>10000</b></td><td headers="hd_h_ml132.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>>10000</b></td><td headers="hd_h_ml132.t2_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>3.3</b></td><td headers="hd_h_ml132.t2_1_1_1_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>5.07</b></td><td headers="hd_h_ml132.t2_1_1_1_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>66.5</b></td><td headers="hd_h_ml132.t2_1_1_1_11" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>58.5</b></td></tr><tr><td headers="hd_h_ml132.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>3</b> (Nitrile ester)</td><td headers="hd_h_ml132.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>43.4</b></td><td headers="hd_h_ml132.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>>10000</b></td><td headers="hd_h_ml132.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">><b>10000</b></td><td headers="hd_h_ml132.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>1570</b></td><td headers="hd_h_ml132.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>>10000</b></td><td headers="hd_h_ml132.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>>10000</b></td><td headers="hd_h_ml132.t2_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>>10000</b></td><td headers="hd_h_ml132.t2_1_1_1_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>1610</b></td><td headers="hd_h_ml132.t2_1_1_1_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>>10000</b></td><td headers="hd_h_ml132.t2_1_1_1_11" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>>10000</b></td></tr><tr><td headers="hd_h_ml132.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>4</b> (Nitrile acid)</td><td headers="hd_h_ml132.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>0.023</b></td><td headers="hd_h_ml132.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>>10000</b></td><td headers="hd_h_ml132.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>13.8</b></td><td headers="hd_h_ml132.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>3.60</b></td><td headers="hd_h_ml132.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>>10000</b></td><td headers="hd_h_ml132.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>>10000</b></td><td headers="hd_h_ml132.t2_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>25.2</b></td><td headers="hd_h_ml132.t2_1_1_1_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>2.17</b></td><td headers="hd_h_ml132.t2_1_1_1_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>89.7</b></td><td headers="hd_h_ml132.t2_1_1_1_11" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>801</b></td></tr><tr><td headers="hd_h_ml132.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>16</b> (Nitrile tetrazole)</td><td headers="hd_h_ml132.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>2.58</b></td><td headers="hd_h_ml132.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>>10000</b></td><td headers="hd_h_ml132.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>1380</b></td><td headers="hd_h_ml132.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>1300</b></td><td headers="hd_h_ml132.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>>10000</b></td><td headers="hd_h_ml132.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>>10000</b></td><td headers="hd_h_ml132.t2_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>>10000</b></td><td headers="hd_h_ml132.t2_1_1_1_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>91.5</b></td><td headers="hd_h_ml132.t2_1_1_1_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>>10000</b></td><td headers="hd_h_ml132.t2_1_1_1_11" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>>10000</b></td></tr><tr><td headers="hd_h_ml132.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>20</b> YVAD-CN</td><td headers="hd_h_ml132.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>2.16</b></td><td headers="hd_h_ml132.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>>10000</b></td><td headers="hd_h_ml132.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>114</b></td><td headers="hd_h_ml132.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>29.0</b></td><td headers="hd_h_ml132.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>>10000</b></td><td headers="hd_h_ml132.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>>10000</b></td><td headers="hd_h_ml132.t2_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>726</b></td><td headers="hd_h_ml132.t2_1_1_1_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>297</b></td><td headers="hd_h_ml132.t2_1_1_1_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>187</b></td><td headers="hd_h_ml132.t2_1_1_1_11" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>116</b></td></tr><tr><td headers="hd_h_ml132.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Ac-LEHD-CHO (standard)</td><td headers="hd_h_ml132.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>15.0</b></td><td headers="hd_h_ml132.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>ND</b></td><td headers="hd_h_ml132.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>81.7</b></td><td headers="hd_h_ml132.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>21.3</b></td><td headers="hd_h_ml132.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>ND</b></td><td headers="hd_h_ml132.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>ND</b></td><td headers="hd_h_ml132.t2_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>3.82</b></td><td headers="hd_h_ml132.t2_1_1_1_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>49.2</b></td><td headers="hd_h_ml132.t2_1_1_1_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>40.4</b></td><td headers="hd_h_ml132.t2_1_1_1_11" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>134</b></td></tr><tr><td headers="hd_h_ml132.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Ac-DEVD-CHO (standard)</td><td headers="hd_h_ml132.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>ND</b></td><td headers="hd_h_ml132.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>3.04</b></td><td headers="hd_h_ml132.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>ND</b></td><td headers="hd_h_ml132.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>ND</b></td><td headers="hd_h_ml132.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>122</b></td><td headers="hd_h_ml132.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>3.54</b></td><td headers="hd_h_ml132.t2_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>ND</b></td><td headers="hd_h_ml132.t2_1_1_1_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>ND</b></td><td headers="hd_h_ml132.t2_1_1_1_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>ND</b></td><td headers="hd_h_ml132.t2_1_1_1_11" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>ND</b></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>a</dt><dd><div id="ml132.tfn3"><p class="no_margin">Data was generated by Reaction Biology (<a href="http://www.reactionbiology.com/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">http://www<wbr style="display:inline-block"></wbr>.reactionbiology.com/</a>). Data is presented as an IC50’s using a (Z-LEHD)2-R110 tetrapeptide substrate for caspase 1, 4, 5, 8, 9, 10, 14 and a (Z-DEVD)2-R110 tetrapeptide substrate for caspase 3, 6 and 7. Data represents the results from three separate experiments.</p></div></dd></dl></div></div></div></div><div id="ml132.s15"><h3>3.5. Cellular Activity</h3><p>Cellular studies have not yet been run with these agents.</p></div><div id="ml132.s16"><h3>3.6. Profiling Assays</h3><p>We have profiled and selected analogs for absorption, distribution, metabolism and elimination (ADME) properties for chosen compounds. As such, 1, 2b, 3, 4 and 16 were submitted to Cyprotex for a profile of bi-directional Caco-2 permeability, plasma protein binding (both human and rat) and microsomal stability (both human and rat) studies (<a class="figpopup" href="/books/NBK56241/table/ml132.t3/?report=objectonly" target="object" rid-figpopup="figml132t3" rid-ob="figobml132t3">Table 3</a>). All agents possessed relatively low A to B permeability; however, the pro-drug <b>1</b> and the ester <b>3</b> had moderately better levels. The high B to A levels reported for <b>1</b> and <b>3</b> strongly suggested an active transport mechanism, and a control experiment with verapamil confirmed that these agents are substrates for Pgp efflux. Unsurprisingly, the free acids <b>2b</b> and <b>4</b> and the tetrazole <b>16</b> had significantly higher free fractions in both human and rat protein binding assays relative to the more hydrophobic prodrug <b>1</b> and ethyl ester <b>3</b>. The clearance rates (Clint) and t<sub>1/2</sub> for <b>2b</b>, <b>3</b>, <b>4</b> and <b>16</b> were all moderate. The ester <b>3</b> was noted to possess a slight degree of degradation in liver microsomes without NADPH as a cofactor, suggesting a non-enzymatic related degradation mechanism. The pro-drug <b>1</b> possessed minimal ability to be metabolized by liver microsomes and a t<sub>1/2</sub> of >9400 minutes. It is unknown how this extended stability affects this agent’s toxicity profile.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml132t3"><a href="/books/NBK56241/table/ml132.t3/?report=objectonly" target="object" title="Table 3" class="img_link icnblk_img figpopup" rid-figpopup="figml132t3" rid-ob="figobml132t3"><img class="small-thumb" src="/books/NBK56241/table/ml132.t3/?report=thumb" src-large="/books/NBK56241/table/ml132.t3/?report=previmg" alt="Table 3. In vitro ADME properties for selected compounds." /></a><div class="icnblk_cntnt"><h4 id="ml132.t3"><a href="/books/NBK56241/table/ml132.t3/?report=objectonly" target="object" rid-ob="figobml132t3">Table 3</a></h4><p class="float-caption no_bottom_margin"><i>In vitro</i> ADME properties for selected compounds. </p></div></div></div></div><div id="ml132.s17"><h2 id="_ml132_s17_">4. Discussion</h2><p>A few areas of SAR were explored around NCGC-00183434/CID-44620939/<a href="/pcsubstance/?term=ML132[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML132</a>. The first investigation was to look at replacement of the 3-chloro-4-anilino-benzene ring with more hydrophobic groups. Replacement of the <i>p</i>-aniline with a <i>p</i>-methoxy or switching to the 3,5-dichlorobenzene resulted in no significant change in activity (compare entries 1, 2 and 4 in <a class="figpopup" href="/books/NBK56241/table/ml132.t1/?report=objectonly" target="object" rid-figpopup="figml132t1" rid-ob="figobml132t1">Table 1</a>). <i>O</i>-substitution resulted in a 5 fold loss in activity (entry 3), while the <i>p</i>-trifluoromethylbenzene analog saw a 10-fold loss in potency. Investigation around the warhead was undertaken and an ethyl ester prodrug was made <i>vide supra</i> as well as a tetrazole version, which is an established carboxylic acid mimetic. As can be seen in <a class="figpopup" href="/books/NBK56241/table/ml132.t2/?report=objectonly" target="object" rid-figpopup="figml132t2" rid-ob="figobml132t2">Table 2</a>, the tetrazole analog had lower activity, but interestingly was slightly more selective than the acid version. As expected, the ester prodrug version (NCGC-00185682) did have slightly better caco-2 permeability <i>vide supra</i> (<a class="figpopup" href="/books/NBK56241/table/ml132.t3/?report=objectonly" target="object" rid-figpopup="figml132t3" rid-ob="figobml132t3">Table 3</a>).</p><div id="ml132.s18"><h3>4.1. Comparison to existing art and how the new probe is an improvement</h3><p>NCGC-00183434/CID-44620939/<a href="/pcsubstance/?term=ML132[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML132</a> is the most potent caspase 1 inhibitor reported to date. It also possesses a unique selectivity pattern relative to other reported caspase inhibitors.</p></div><div id="ml132.s19"><h3>4.2. Mechanism of Action Studies</h3><p>We examined the binding mechanism of these agents through molecular modeling. Several crystal structures of caspase 1 exist, including structures with reversible and non-reversible inhibitors (PDB codes: 1BMQ, 1IBC, 1ICE, 1RWK, 1RWM, 1RWN, 1RWO, 1RWP, 1RWV, 1RWW, 1RWX, 1SC1, 1SC3, 1SC4, 2FQQ, 2H48, 2HBQ, 2HBR, 2HBY, 2HBZ, 2FQR, 2FQS, 2FQU, 2FQZ) [<a class="bk_pop" href="#ml132.r8" data-bk-pop-others="ml132.r9 ml132.r10 ml132.r11">8–11</a>]. We identified 2HBQ as the best template for <b>4</b> (2HBQ is a co-crystal of caspase 1 and <i>Z</i>-<i>VAD</i>-<i>FMK</i>). We applied the presumption of a covalent reversible mechanism of inhibition when building a model for binding of <b>4</b>. The nitrile carbon was therefore held at a proximal distance (2.6 Å) from the catalytic cysteine residue (C285) by constraint docking, and flexibility was granted to the remainder of the small molecule to achieve an optimal binding pose using FRED [<a class="bk_pop" href="#ml132.r12">12</a>]. The results are shown in <a class="figpopup" href="/books/NBK56241/figure/ml132.f4/?report=objectonly" target="object" rid-figpopup="figml132f4" rid-ob="figobml132f4">figure 4</a> and demonstrate complementarity between the peptidic fragment of <b>4</b> and the peptide binding domain of caspase 1. Key interactions were noted for the acid moiety and arginine residues 341 and 179 in similar fashion to other Asp containing small molecule caspase 1 inhibitors. While direct interrogation of a covalent interaction between the nitrile and C285 was not pursued in our model, this representation does illustrate the open binding cavity that accommodates the tetrahedral intermediate that forms as a result of covalent binding with aldehyde based inhibitors (a mimetic of the hemithiolacetal intermediate associated with transition state 1 (TS1) during proteolysis). In contrast, covalent interactions between a thiol and a nitrile form a thioimidate intermediate that mimics transition state 2 (TS2) of an enzymatic proteolytic event between a cysteine proteases and a substrate. Ménard and coworkers examined aldehyde and nitrile inhibitors of papain and found that the thioimidate intermediate engages the oxyanion hole interaction in a manner that more closely mimics the natural process of hydrolysis during proteolysis [<a class="bk_pop" href="#ml132.r13">13</a>]. This may have consequences for both the binding affinity of nitrile-based cysteine proteases inhibitors and their ultimate resolution through hydrolysis of the thioimidate intermediate.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml132f4" co-legend-rid="figlgndml132f4"><a href="/books/NBK56241/figure/ml132.f4/?report=objectonly" target="object" title="Figure 4" class="img_link icnblk_img figpopup" rid-figpopup="figml132f4" rid-ob="figobml132f4"><img class="small-thumb" src="/books/NBK56241/bin/ml132f4.gif" src-large="/books/NBK56241/bin/ml132f4.jpg" alt="Figure 4. Molecular model (ribbon and space filling) of NCGC-00183434/CID-44620939/ML132 (4) bound to caspase 1." /></a><div class="icnblk_cntnt" id="figlgndml132f4"><h4 id="ml132.f4"><a href="/books/NBK56241/figure/ml132.f4/?report=objectonly" target="object" rid-ob="figobml132f4">Figure 4</a></h4><p class="float-caption no_bottom_margin">Molecular model (ribbon and space filling) of NCGC-00183434/CID-44620939/ML132 (<i>4</i>) bound to caspase 1. </p></div></div></div><div id="ml132.s20"><h3>4.3. Planned Future Studies</h3><p>Recently, the Petsko and Ringe labs have identified the human enzyme caspase-1 as the protease that cleaves α-synuclein <i>in vivo</i>, producing a C-terminal truncated fragment that nucleates the aggregation of αS. Synucleinopathies are a class of neurologic disorders that together afflict millions of Americans. They are characterized by neurocytoplasmic inclusions containing primarily α-synuclein, an abundant neuronal protein whose cellular functions are poorly understood. The most prevalent synucleinopathy is Parkinson’s disease, a devastating neurodegenerative condition that kills dopaminergic neurons, leading to tremor, slowness of movement, and eventual paralysis and death. We plan to continue our optimization of the existing probe compound in a manner that will allow it to penetrate the blood-brain barrier, thus allowing the Wells and Petsko labs to examine the role of caspase 1 in synucleinopathies, including Parkinson’s disease.</p><div id="ml132.s21"><h4>Probe properties</h4><div id="ml132.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/NBK56241/table/ml132.tu3/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml132.tu3_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml132.tu3_1_1_1_1" rowspan="2" colspan="1" headers="hd_h_ml132.tu3_1_1_1_1" style="text-align:center;vertical-align:middle;">Calculated Property</th><th id="hd_h_ml132.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">Probe Identity</th></tr><tr><th headers="hd_h_ml132.tu3_1_1_1_2" id="hd_h_ml132.tu3_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">CID_44620939 (MLS003178557)</th></tr></thead><tbody><tr><td headers="hd_h_ml132.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_ml132.tu3_1_1_1_2 hd_h_ml132.tu3_1_1_2_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">477.94122</td></tr><tr><td headers="hd_h_ml132.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Molecular Formula</td><td headers="hd_h_ml132.tu3_1_1_1_2 hd_h_ml132.tu3_1_1_2_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">C22H28ClN5O5</td></tr><tr><td headers="hd_h_ml132.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">XLogP3-AA</td><td headers="hd_h_ml132.tu3_1_1_1_2 hd_h_ml132.tu3_1_1_2_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">1.6</td></tr><tr><td headers="hd_h_ml132.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H-Bond Donor</td><td headers="hd_h_ml132.tu3_1_1_1_2 hd_h_ml132.tu3_1_1_2_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">4</td></tr><tr><td headers="hd_h_ml132.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H-Bond Acceptor</td><td headers="hd_h_ml132.tu3_1_1_1_2 hd_h_ml132.tu3_1_1_2_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">7</td></tr><tr><td headers="hd_h_ml132.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Rotatable Bond Count</td><td headers="hd_h_ml132.tu3_1_1_1_2 hd_h_ml132.tu3_1_1_2_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">8</td></tr><tr><td headers="hd_h_ml132.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Tautomer Count</td><td headers="hd_h_ml132.tu3_1_1_1_2 hd_h_ml132.tu3_1_1_2_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">10</td></tr><tr><td headers="hd_h_ml132.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Exact Mass</td><td headers="hd_h_ml132.tu3_1_1_1_2 hd_h_ml132.tu3_1_1_2_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">477.177897</td></tr><tr><td headers="hd_h_ml132.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MonoIsotopic Mass</td><td headers="hd_h_ml132.tu3_1_1_1_2 hd_h_ml132.tu3_1_1_2_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">477.177897</td></tr><tr><td headers="hd_h_ml132.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_ml132.tu3_1_1_1_2 hd_h_ml132.tu3_1_1_2_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">166</td></tr><tr><td headers="hd_h_ml132.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Heavy Atom Count</td><td headers="hd_h_ml132.tu3_1_1_1_2 hd_h_ml132.tu3_1_1_2_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">33</td></tr><tr><td headers="hd_h_ml132.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Formal Charge</td><td headers="hd_h_ml132.tu3_1_1_1_2 hd_h_ml132.tu3_1_1_2_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml132.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Isotope Atom Count</td><td headers="hd_h_ml132.tu3_1_1_1_2 hd_h_ml132.tu3_1_1_2_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml132.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_ml132.tu3_1_1_1_2 hd_h_ml132.tu3_1_1_2_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">3</td></tr><tr><td headers="hd_h_ml132.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_ml132.tu3_1_1_1_2 hd_h_ml132.tu3_1_1_2_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml132.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_ml132.tu3_1_1_1_2 hd_h_ml132.tu3_1_1_2_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml132.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_ml132.tu3_1_1_1_2 hd_h_ml132.tu3_1_1_2_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml132.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_ml132.tu3_1_1_1_2 hd_h_ml132.tu3_1_1_2_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">1</td></tr><tr><td headers="hd_h_ml132.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Complexity</td><td headers="hd_h_ml132.tu3_1_1_1_2 hd_h_ml132.tu3_1_1_2_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">820</td></tr></tbody></table></div></div></div></div></div><div id="ml132.s22"><h2 id="_ml132_s22_">5. References</h2><dl class="temp-labeled-list"><dt>1.</dt><dd><div class="bk_ref" id="ml132.r1">Martinon F, Tschopp J. <span><span class="ref-journal">Cell. </span>2004;<span class="ref-vol">117</span>:561–574.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15163405" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15163405</span></a>]</div></dd><dt>2.</dt><dd><div class="bk_ref" id="ml132.r2">Braddock M, Quinn A. <span><span class="ref-journal">Nat. Rev Drug Discovery. </span>2004;<span class="ref-vol">3</span>:1–10.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15060528" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15060528</span></a>]</div></dd><dt>3.</dt><dd><div class="bk_ref" id="ml132.r3">Linton SD. <span><span class="ref-journal">Curr. Top. Med. Chem. </span>2005;<span class="ref-vol">5</span>:1697–1717.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16375749" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16375749</span></a>]</div></dd><dt>4.</dt><dd><div class="bk_ref" id="ml132.r4">Falgueyret J-P, Oballa RM, Okamoto O, Wesolowski G, Aubin Y, Rydzewski RM, Prasit P, Riendeau D, Rodan SB, Percival MD. <span><span class="ref-journal">J. Med. Chem. </span>2001;<span class="ref-vol">44</span>:94–104.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11141092" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11141092</span></a>]</div></dd><dt>5.</dt><dd><div class="bk_ref" id="ml132.r5">Mallari JP, Shelat AA, Obrien T, Caffrey CR, Kosinski A, Connelly M, Harbut M, Greenbaum D, McKerrow JH, Guy RK. <span><span class="ref-journal">J. Med. Chem. </span>2008;<span class="ref-vol">51</span>:545–552.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18173229" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18173229</span></a>]</div></dd><dt>6.</dt><dd><div class="bk_ref" id="ml132.r6">Mott BT, Ferreira R, Simeonov A, Jadhav A, Ang K-H, Leister W, Shen M, Silveira JT, McKerrow JH, Inglese J, Austin CP, Thomas CJ, Shoichet BK, Maloney DJ. <span><span class="ref-journal">J. Med. Chem. </span>2010;<span class="ref-vol">53</span>:52–60.</span> [<a href="/pmc/articles/PMC2804034/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2804034</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19908842" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19908842</span></a>]</div></dd><dt>7.</dt><dd><div class="bk_ref" id="ml132.r7">Wannamaker W, Davies R, Namchuk M, Pollard J, Ford P, Ku G, Decker C, Charifson P, Weber P, Germann UA, Kuida K, Randle JCR. <span><span class="ref-journal">J. Pharmacol. Exp. Ther. </span>2007;<span class="ref-vol">321</span>:509–516.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17289835" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17289835</span></a>]</div></dd><dt>8.</dt><dd><div class="bk_ref" id="ml132.r8">Wilson KP, Black J-AF, Thomason JA, Kim EE, Griffith JP, Navia MA, Murcko MA, Chambers SP, Aldape RA, Raybuck SA, Libingston DJ. <span><span class="ref-journal">Nature. </span>1994;<span class="ref-vol">370</span>:270–275.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/8035875" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8035875</span></a>]</div></dd><dt>9.</dt><dd><div class="bk_ref" id="ml132.r9">Okamoto Y, Anan H, Nakai E, Morihira K, Yonetoku Y, Kurihara H, Sakashita H, Terai Y, Takeuchi M, Shibanuma T, Isomura Y. <span><span class="ref-journal">Chem. Pharm. Bull. </span>1999;<span class="ref-vol">47</span>:11–21.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9987822" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9987822</span></a>]</div></dd><dt>10.</dt><dd><div class="bk_ref" id="ml132.r10">Romanowski MJ, Scheer JM, O’Brien T, McDowell RS. <span><span class="ref-journal">Structure. </span>2004;<span class="ref-vol">12</span>:1361–1371.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15296730" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15296730</span></a>]</div></dd><dt>11.</dt><dd><div class="bk_ref" id="ml132.r11">Scheer JM, Romanowski MJ, Wells JA. <span><span class="ref-journal">Proc. Nat. Acad. Sci. U. S. A. </span>2006;<span class="ref-vol">103</span>:7595–7600.</span> [<a href="/pmc/articles/PMC1458511/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1458511</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/16682620" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16682620</span></a>]</div></dd><dt>12.</dt><dd><div class="bk_ref" id="ml132.r12">Santa Fe, NM: OpenEye Scientific Software, Inc.; <a href="http://www.eyesopen.com/" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">http://www<wbr style="display:inline-block"></wbr>.eyesopen.com/</a></div></dd><dt>13.</dt><dd><div class="bk_ref" id="ml132.r13">Dufour E, Storer AC, Ménard R. <span><span class="ref-journal">Biochemistry. </span>1995;<span class="ref-vol">34</span>:9136–9143.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/7619812" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7619812</span></a>]</div></dd></dl></div><div style="display:none"><div style="display:none" id="figml132f5"><img alt="Image ml132f5" src-large="/books/NBK56241/bin/ml132f5.jpg" /></div><div style="display:none" id="figml132f6"><img alt="Image ml132f6" src-large="/books/NBK56241/bin/ml132f6.jpg" /></div></div><div id="bk_toc_contnr"></div></div></div>
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<div xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Views</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="PDF_download" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="/books/NBK56241/?report=reader">PubReader</a></li><li><a href="/books/NBK56241/?report=printable">Print View</a></li><li><a data-jig="ncbidialog" href="#_ncbi_dlg_citbx_NBK56241" data-jigconfig="width:400,modal:true">Cite this Page</a><div id="_ncbi_dlg_citbx_NBK56241" style="display:none" title="Cite this Page"><div class="bk_tt">Boxer MB, Shen M, Auld DS, et al. A small molecule inhibitor of Caspase 1. 2010 Feb 25 [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></div></div></li><li><a href="/books/NBK56241/pdf/Bookshelf_NBK56241.pdf">PDF version of this page</a> (529K)</li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>In this Page</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="page-toc" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="#ml132.s1" ref="log$=inpage&link_id=inpage">Probe Structure & Characteristics</a></li><li><a href="#ml132.s2" ref="log$=inpage&link_id=inpage">Recommendations for scientific use of the probe</a></li><li><a href="#ml132.s3" ref="log$=inpage&link_id=inpage">Introduction</a></li><li><a href="#ml132.s4" ref="log$=inpage&link_id=inpage">Materials and Methods</a></li><li><a href="#ml132.s9" ref="log$=inpage&link_id=inpage">Results</a></li><li><a href="#ml132.s17" ref="log$=inpage&link_id=inpage">Discussion</a></li><li><a href="#ml132.s22" ref="log$=inpage&link_id=inpage">References</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Related information</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="discovery_db_links" id="Shutter"></a></div><div class="portlet_content"><ul><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pmc&DbFrom=books&Cmd=Link&LinkName=books_pmc_refs&IdsFromResult=2510508" ref="log$=recordlinks">PMC</a><div class="brieflinkpop offscreen_noflow">PubMed Central citations</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pcassay&DbFrom=books&Cmd=Link&LinkName=books_pcassay_probe&IdsFromResult=2510508" ref="log$=recordlinks">PubChem BioAssay for Chemical Probe</a><div class="brieflinkpop offscreen_noflow">PubChem BioAssay records reporting screening data for the development of the chemical probe(s) described in this book chapter</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pcsubstance&DbFrom=books&Cmd=Link&LinkName=books_pcsubstance&IdsFromResult=2510508" ref="log$=recordlinks">PubChem Substance</a><div class="brieflinkpop offscreen_noflow">Related PubChem Substances</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pubmed&DbFrom=books&Cmd=Link&LinkName=books_pubmed_refs&IdsFromResult=2510508" ref="log$=recordlinks">PubMed</a><div class="brieflinkpop offscreen_noflow">Links to PubMed</div></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Similar articles in PubMed</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="PBooksDiscovery_RA" id="Shutter"></a></div><div class="portlet_content"><ul><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20229566" ref="ordinalpos=1&linkpos=1&log$=relatedarticles&logdbfrom=pubmed">A highly potent and selective caspase 1 inhibitor that utilizes a key 3-cyanopropanoic acid moiety.</a><span class="source">[ChemMedChem. 2010]</span><div class="brieflinkpop offscreen_noflow">A highly potent and selective caspase 1 inhibitor that utilizes a key 3-cyanopropanoic acid moiety.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Boxer MB, Quinn AM, Shen M, Jadhav A, Leister W, Simeonov A, Auld DS, Thomas CJ. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">ChemMedChem. 2010 May 3; 5(5):730-8. </em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/18387304" ref="ordinalpos=1&linkpos=2&log$=relatedarticles&logdbfrom=pubmed">Structure-based discovery of a novel non-peptidic small molecular inhibitor of caspase-3.</a><span class="source">[Bioorg Med Chem. 2008]</span><div class="brieflinkpop offscreen_noflow">Structure-based discovery of a novel non-peptidic small molecular inhibitor of caspase-3.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Sakai J, Yoshimori A, Nose Y, Mizoroki A, Okita N, Takasawa R, Tanuma S. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">Bioorg Med Chem. 2008 May 1; 16(9):4854-9. 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