Open AccessDiscovery and Optimization of 2H-1λ2-Pyridin-2-one Inhibitors of Mutant Isocitrate Dehydrogenase 1 for the Treatment of Cancer
Author(s) -
Jason M. Rohde,
Karavadhi Surendra,
Rajan Pragani,
Li Liu,
Yuhong Fang,
Weihe Zhang,
Andrew L. McIver,
Hongchao Zheng,
Qingyang Liu,
Mindy I. Davis,
Daniel J. Urban,
Tobie D. Lee,
Dorian M. Cheff,
Melinda G. Hollingshead,
Mark J. Henderson,
Natalia J. Martinez,
Kyle R. Brimacombe,
Adam Yasgar,
Wei Zhao,
Carleen KlumppThomas,
Sam Michael,
Joseph M. Covey,
William Moore,
Gordon M. Stott,
Zhuyin Li,
Anton Simeonov,
Ajit Jadhav,
Stephen V. Frye,
Matthew D. Hall,
Min Shen,
Xiaodong Wang,
Samarjit Patnaik,
Matthew B. Boxer
Publication year - 2021
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.1c00019
Subject(s) - isocitrate dehydrogenase , idh1 , chemistry , mutant , quinoline , myeloid leukemia , cancer research , metabolite , enzyme , pharmacology , stereochemistry , biochemistry , medicine , gene , organic chemistry
Neomorphic mutations in isocitrate dehydrogenase 1 (IDH1) are oncogenic for a number of malignancies, primarily low-grade gliomas and acute myeloid leukemia. We report a medicinal chemistry campaign around a 7,7-dimethyl-7,8-dihydro-2 H -1λ 2 -quinoline-2,5(6 H )-dione screening hit against the R132H and R132C mutant forms of isocitrate dehydrogenase (IDH1). Systematic SAR efforts produced a series of potent pyrid-2-one mIDH1 inhibitors, including the atropisomer (+)-119 ( NCATS - SM5637 , NSC 791985 ). In an engineered mIDH1-U87-xenograft mouse model, after a single oral dose of 30 mg/kg, 16 h post dose, between 16 and 48 h, (+)-119 showed higher tumoral concentrations that corresponded to lower 2-HG concentrations, when compared with the approved drug AG-120 (ivosidenib).