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HTS of IDH1 R132H leads to identification of a potent inhibitor of IDH1 R132H capable of reducing 2-hydroxyglutarate production in U87-MG glioblastoma cells

Wednesday, September 24, 2014 — Poster Session IV

10:00 a.m. –12:00 p.m.

FAES Academic Center




  • MI Davis
  • R Pragani
  • S Gross
  • J Popovici-Muller
  • K Straley
  • W Lea
  • Z Li
  • L Dang
  • M Shen
  • MB Boxer
  • A Simeonov


Mutations (R132H or R132C) in the active site of isocitrate dehydrogenase (IDH1) have been associated with a number of cancers, including acute myeloid leukemia and glioblastoma. These mutations result in loss of activity for metabolism of isocitrate, but confer gain-of-function for the production of the oncometabolite 2-hydroxyglutarate (2-HG). Herein we describe the quantitative high-throughput screening of IDH1 R132H. A diverse library of 387,602 compounds was screened as six-point dilution series, yielding several validated inhibitory series. Results from the screen will be presented, along with the characterization of a phenylglycine probe. A member of the series, ML309, is a potent and selective inhibitor of mutant IDH1 and effectively lowers cell-based production of 2-HG in a U87-MG IDH1 R132H glioblastoma cell line. ML309 is competitive with respect to α-KG and uncompetitive with respect to NADPH, which had also been reported for another member of the phenylglycine series.

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