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 ( S , S )-diastereomer ( IDH125 , 1f ) 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 ( S , S )-oxazolidinone IDH889 ( 5x ) with good exposure and 2-HG inhibitory activity in a mutant IDH1 xenograft mouse model.
Competing Interests: The authors declare no competing financial interest.