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Publication Abstract from PubMed

Mutations at the arginine residue (R132) in isocitrate dehydrogenase 1 (IDH1) are frequently identified in various human cancers. Inhibition of mutant IDH1 (mIDH1) with small molecules has been clinically validated as a promising therapeutic treatment for acute myeloid leukemia and multiple solid tumors. Herein we report the discovery and optimization of a series of quinolinones to provide potent and orally bioavailable mIDH1 inhibitors with selectivity over wild type IDH1. The X-ray structure of an early lead 24 in complex with mIDH1-R132H shows that the inhibitor unexpectedly binds to an allosteric site. Efforts to improve the in vitro and in vivo ADME properties of 24 yielded a preclinical candidate 63. The detailed preclinical ADME and pharmacology studies of 63 support further development of quinolinone-based mIDH1 inhibitors as therapeutic agents in human trials.

Discovery and Optimization of Quinolinone Derivatives as Potent, Selective and Orally Bioavailable mutant Isocitrate Dehydrogenase 1 (mIDH1) Inhibitors.,Lin J, Lu W, Caravella JA, Campbell AM, Diebold RB, Ericsson A, Fritzen E, Gustafson GR, Lancia DR, Shelekhin T, Wang Z, Castro J, Clarke A, Gotur D, Josephine HR, Katz M, Diep H, Kershaw M, Yao L, Kauffman G, Hubbs SE, Luke GP, Toms AV, Wang L, Bair KW, Barr KJ, Dinsmore CJ, Walker D, Ashwell S J Med Chem. 2019 Jun 14. doi: 10.1021/acs.jmedchem.9b00362. PMID:31199148^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.