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.
Julian R Levell  1 ,  Thomas Caferro  1 ,  Gregg Chenail  1 ,  Ina Dix  1 ,  Julia Dooley  1 ,  Brant Firestone  1 ,  Pascal D Fortin  1 ,  John Giraldes  1 ,  Ty Gould  1 ,  Joseph D Growney  1 ,  Michael D Jones  1 ,  Raviraj Kulathila  1 ,  Fallon Lin  1 ,  Gang Liu  1 ,  Arne Mueller  1 ,  Simon van der Plas  1 ,  Kelly Slocum  1 ,  Troy Smith  1 ,  Remi Terranova  1 ,  B Barry Touré  1 ,  Viraj Tyagi  1 ,  Trixie Wagner  1 ,  Xiaoling Xie  1 ,  Ming Xu  1 ,  Fan S Yang  1 ,  Liping X Zhou  1 ,  Raymond Pagliarini  1 ,  Young Shin Cho  1
Affiliations
  • 1. Novartis Institutes for Biomedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
PMID: 28197303 DOI: 10.1021/acsmedchemlett.6b00334
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 IDH1R132H. 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 IDH1wt. 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.
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