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; tumor 2-HG; R132H IDH1 inhibitors