Optimization of 3-Pyrimidin-4-yl-oxazolidin-2-ones as Allosteric and Mutant Specific Inhibitors of IDH1

High throughput screeningand subsequent hit validation identified4-isopropyl-3-(2-((1-phenylethyl)amino)pyrimidin-4-yl) oxazolidin-2-one as a potent inhibitor of IDH1R132H. Synthesis of the four separate stereoisomers identifiedthe (S,S)- diastereomer(IDH125, 1f) as the most potent isomer. This also showed reasonable cellular activity and excellent selectivity vs IDH1wt. Initial structure–activity relationship exploration identifiedthe key tolerances and potential for optimization. X-ray crystallography identifieda functionally relevant allosteric binding site amenable to inhibitors, which can penetrate the blood–brain barrier, and aided rational optimization. Potency improvement and modulation of the physicochemical properties identified(S,S)-oxazolidinone IDH889 (5x) with good exposure and 2-HG inhibitory activity in a mutant IDH1xenograft mouse model.