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Discovery of a potent, small molecule inhibitor of R132H mutant isocitrate dehydrogenase 1.

Wednesday, October 10, 2012 — Poster Session II

Noon – 2:00 p.m

Natcher Conference Center, Building 45




  • R. Pragani
  • M. Davis
  • N. Thorne
  • A. Simeonov
  • M. Shen
  • M.B. Boxer


The role of isocitrate dehydrogenase (IDH) in cancer has emerged from the sequencing of over 900 tumors which revealed mutations of either IDH1 or IDH2 in up to 70% of secondary gliomas and in 17% of 893 newly diagnosed acute myeloid leukemia (AML) cases. In IDH1, the most common mutation is the substitution of the active site arginine 132 for a histidine or cysteine residue. This results in loss-of-function for the metabolism of isocitrate but confers gain-of-function for oncometabolite 2-hydroxyglutarate (2-HG) production. Herein, we describe the quantitative high throughput screening of the R132H mutant IDH1 enzyme against the MLPCN compound library and the ensuing medicinal chemistry optimization of a small molecule hit. The resulting optimized molecule, ML309, is a potent, selective inhibitor of R132H mutant IDH1 and also lowers production of 2-HG in a U87MG mutant glioblastoma cell line. ML309 will hopefully serve as a tool to uncover the role of IDH1 as an oncogene, 2-HG as an oncometabolite, and possibly uncover much needed therapies for glioma and AML patients in the future.

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