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 IDH1R132H. Synthesis of the 4 separate diastereomers identified the (S,S)-diastereomer (IDH125) as the most potent isomer. This also showed reasonable cellular activity and excellent selectivity vs IDH1wt. Initial SAR 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 physico-chemical properties identified (S)-3-(2-(((S)-1-(5-(4-fluoro-3-methylphenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one (IDH889) with good in-vivo exposure and in-vivo activity in a mutant IDH1 xenograft mouse model. identified the (S,S)-diastereomer (IDH125) as the most potent isomer. This also showed reasonable cellular activity and excellent selectivity vs IDH1wt. Initial SAR 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 physico-chemical properties identified (S)-3-(2-(((S)-1-(5-(4-fluoro-3-methylphenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one (IDH889) with good in-vivo exposure and in-vivo activity in a mutant IDH1 xenograft mouse model 30 samples from cell culture with one or two replicates. Possible controls are treated with DMSO, other comparsions can be made between WT and mutant cell lines.