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<article><div class="banner banner--gray banner--compact" style="--banner-background-image: url('/sites/default/files/media/image/2021-03/2015.jpg');--banner-background-focus: 50% 50%"><div class="banner__wrapper"><div class="banner__container"><h2 class="banner__heading">NIH Research Festival</h2><div class="banner__content"><p><strong><time datetime="2015-09-16">September 16</time> – <time datetime="2015-09-18">18, 2015</time></strong></p></div></div></div></div></article>
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<div class="section"><div data-drupal-messages-fallback class="hidden"></div></div><main role="main"><div id="main-content" tabindex="-1"></div><div class="section"><div class="content-sidebar"><div class="content-sidebar__main"><div class="content-sidebar__main-content"><div id="block-mainpagecontent-2"><article><h1>Pharmacokinetic Evaluation of Potent Mutant IDH1 Inhibitors in Discovery Research</h1><div class="schedule"><div class="schedule__label"><div class="schedule__label-text"><time datetime="2015-09-16">Wednesday, September 16, 2015</time>
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– Poster Session I
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</div></div><div class="schedule__content"><div class="schedule__item"><div class="schedule__time">3:30 – 5:00 p.m.</div><div class="schedule__description"><p><strong>FAES Terrace</strong></p></div><div class="schedule__description"><p><strong>NCATS</strong></p></div><div class="schedule__description"><p><strong>RSCHSUPP-15</strong></p></div></div></div></div><h2>Authors</h2><ul><li>EA Hughes</li><li>J Rohde</li><li>MI Davis</li><li>MB Boxer</li><li>X Xu</li><li>AQ Wang</li></ul><h2>Abstract</h2><p>Mutations (R123H or R123C) of isocitrate dehydrogenase 1 (IDH1) are a common feature of many cancers. This study focused on applications of pharmacokinetic (PK) concepts in selecting compounds that targeted IDH1 mutations for glioblastomas. PK studies provide essential information on the absorption, distribution, metabolism and excretion properties that govern in vivo exposures of potential therapeutics. PK studies in CD-1 mice were utilized to rank mutant IDH1 inhibitors from a newly optimized series of compounds. A lead compound was selected based upon the relatively high exposure (AUC) and long half-life in brain, the target organ. Additional studies were performed on the lead compound in female severe combined immunodeficiency (SCID) mice, a background strain used for efficacy studies. Five inhibitors were quantified in plasma and brain of CD-1 mice when administered at 3mg/kg via IV and oral routes. The brain exposure of these inhibitors ranged from 7 to 193ng.hr/mL and the half-life ranged from 2.7 to 3.4hrs. The lead compound NCGC751 showed the highest brain exposure of 193ng.hr/mL and a relatively long half-life of 3.2hrs. When dosed at 30mg/kg orally in SCID mice, NCGC751 showed a marked increase in brain exposure of 8,740ng.hr/mL and a long half-life of 5.7hrs. From in vitro cell based assays, the IC50 of NCGC751 ranged from 25 to 118ng/mL depending on the mutation. Thus, brain concentrations of NCGC751 remained above 118ng/mL for 24hrs (533ng/mL at 24hrs) in SCID mice. This compound is recommended as a Proof-of-Concept study candidate for in vivo efficacy evaluations.</p><p><strong>Scientific Focus Area</strong>: Research Support Services</p><p class="updated"><small>This page was last updated on Friday, March 26, 2021</small></p></article>
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