2. Academic Validation
  3. Assessing inhibitors of mutant isocitrate dehydrogenase using a suite of pre-clinical discovery assays

Assessing inhibitors of mutant isocitrate dehydrogenase using a suite of pre-clinical discovery assays

  • Sci Rep. 2017 Oct 6;7(1):12758. doi: 10.1038/s41598-017-12630-x.
Daniel J Urban 1,  Natalia J Martinez 1,  Mindy I Davis 1,  Kyle R Brimacombe 1,  Dorian M Cheff 1,  Tobie D Lee 1,  Mark J Henderson 1,  Steven A Titus 1,  Rajan Pragani 1,  Jason M Rohde 1,  Li Liu 1,  Yuhong Fang 1,  Surendra Karavadhi 1,  Pranav Shah 1,  Olivia W Lee 1,  Amy Wang 1,  Andrew McIver 2,  Hongchao Zheng 2,  Xiaodong Wang 2,  Xin Xu 1,  Ajit Jadhav 1,  Anton Simeonov 1,  Min Shen 1,  Matthew B Boxer 1,  Matthew D Hall 3
Affiliations

Affiliations

  • 1 NCATS Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland, 20850, United States.
  • 2 Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina School of Medicine, Chapel Hill, 27599, North Carolina, United States.
  • 3 NCATS Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland, 20850, United States. [email protected].
PMID: 28986582 DOI: 10.1038/s41598-017-12630-x
Abstract

Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are key metabolic enzymes that are mutated in a variety of cancers to confer a gain-of-function activity resulting in the accumulation of an oncometabolite, D-2-hydroxyglutarate (2-HG). Accumulation of 2-HG can result in epigenetic dysregulation and a block in cellular differentiation, suggesting these mutations play a role in neoplasia. Based on its potential as a Cancer target, a number of small molecule inhibitors have been developed to specifically inhibit mutant forms of IDH (mIDH1 and mIDH2). We present a comprehensive suite of in vitro preclinical drug development assays that can be used as a tool-box to identify lead compounds for mIDH drug discovery programs, as well as what we believe is the most comprehensive publically available dataset on the top mIDH inhibitors. This involved biochemical, cell-based, and tier-one ADME techniques.

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