Discovery of Potent Small Molecule Inhibitors of Mutant Isocitrate Dehydrogenase 1

Authors

• S Karavadhi
• JM Rohde
• R Pragani
• M Davis
• D Urban
• N Martinez
• T Lee
• D Cheff
• K Brimacombe
• L Liu
• M Henderson
• S Titus
• Y Fang
• P Shah
• J Covey
• M Davis
• M Hollingshead
• WJ Moore
• A Mclver
• H Zheng

Abstract

The mutated form of a key metabolic enzyme, isocitrate dehydrogenase (IDH), has emerged as a prominent oncology target given its prevalence in a diversity of cancers. The mutation of an active site arginine residue confers neomorphic activity to mutant isocitrate dehydrogenase (mIDH) and ultimately leads to the production of 2-hydroxyglutarate (2-HG), an oncometabolite which may be involved in the reprogramming of cells for tumorigenesis. In an effort to develop treatments for mIDH1 cancers, NCATS conducted a qHTS to identify inhibitors of both the R132H and the R132C IDH1 mutants. Subsequent medicinal chemistry optimization led to the discovery of potent inhibitors that minimize the production of 2-HG both in vitro and in vivo. Top compounds within this campaign continue to be interrogated in vivo in order to select a candidate for advancement into preclinical development.

Scientific Focus Area: Chemical Biology

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