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	NCATS	CHEM-11

Authors

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

Abstract

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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