| Literature DB >> 28197303 |
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.
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.Entities:
Keywords: 2-HG; 3-pyrimidin-4-yloxazolidin-2-one; Mutant IDH1 inhibitor; allosteric inhibition; chirality-defined potency; preclinical in vivo activity
Year: 2016 PMID： 28197303 PMCID： PMC5304300 DOI： 10.1021/acsmedchemlett.6b00334
Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345