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

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

Affiliation

  • 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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