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

High throughput screening and subsequent hit validation identified 4-isopropyl-3-(2-((1-phenylethyl)amino)pyrimidin-4-yl)oxazolidin-2-one as a potent inhibitor of IDH1^R132H. Synthesis of the four separate stereoisomers identified the (<i>S</i>,<i>S</i>)-diastereomer (<b>IDH125</b>, <b>1f</b>) as the most potent isomer. This also showed reasonable cellular activity and excellent selectivity vs IDH1^wt. Initial structure-activity relationship exploration identified the key tolerances and potential for optimization. X-ray crystallography identified a 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 (<i>S</i>,<i>S</i>)-oxazolidinone <b>IDH889</b> (<b>5x</b>) with good exposure and 2-HG inhibitory activity in a mutant IDH1 xenograft mouse model.