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

Julian R Levell; Thomas Caferro; Gregg Chenail; Ina Dix; Julia Dooley; Brant Firestone; Pascal D Fortin; John Giraldes; Ty Gould; Joseph D Growney; Michael D Jones; Raviraj Kulathila; Fallon Lin; Gang Liu; Arne Mueller; Simon van der Plas; Kelly Slocum; Troy Smith; Remi Terranova; B Barry Touré; Viraj Tyagi; Trixie Wagner; Xiaoling Xie; Ming Xu; Fan S Yang; Liping X Zhou; Raymond Pagliarini; Young Shin Cho

doi:10.1021/acsmedchemlett.6b00334

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

ACS Med Chem Lett. 2016 Dec 16;8(2):151-156. doi: 10.1021/acsmedchemlett.6b00334. eCollection 2017 Feb 9.

Authors

Julian R Levell¹, Thomas Caferro¹, Gregg Chenail¹, Ina Dix¹, Julia Dooley¹, Brant Firestone¹, Pascal D Fortin¹, John Giraldes¹, Ty Gould¹, Joseph D Growney¹, Michael D Jones¹, Raviraj Kulathila¹, Fallon Lin¹, Gang Liu¹, Arne Mueller¹, Simon van der Plas¹, Kelly Slocum¹, Troy Smith¹, Remi Terranova¹, B Barry Touré¹, Viraj Tyagi¹, Trixie Wagner¹, Xiaoling Xie¹, Ming Xu¹, Fan S Yang¹, Liping X Zhou¹, Raymond Pagliarini¹, Young Shin Cho¹

Affiliation

¹ Novartis Institutes for Biomedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.

Abstract

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.

Keywords: 2-HG; 3-pyrimidin-4-yloxazolidin-2-one; Mutant IDH1 inhibitor; allosteric inhibition; chirality-defined potency; preclinical in vivo activity.