Discovery of the First Potent Inhibitors of Mutant IDH1 That Lower Tumor 2-HG in Vivo

ACS Med Chem Lett. 2012 Sep 17;3(10):850-5. doi: 10.1021/ml300225h. eCollection 2012 Oct 11.


Optimization of a series of R132H IDH1 inhibitors from a high throughput screen led to the first potent molecules that show robust tumor 2-HG inhibition in a xenograft model. Compound 35 shows good potency in the U87 R132H cell based assay and ∼90% tumor 2-HG inhibition in the corresponding mouse xenograft model following BID dosing. The magnitude and duration of tumor 2-HG inhibition correlates with free plasma concentration.

Keywords: Mutant IDH1; R132H IDH1 inhibitors; tumor 2-HG.