Discovery and Optimization of 2H-1λ2-Pyridin-2-one Inhibitors of Mutant Isocitrate Dehydrogenase 1 for the Treatment of Cancer

作者：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 Klumpp‐Thomas, 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 · 发表于：Journal of Medicinal Chemistry · 年份：2021 · DOI：10.1021/acs.jmedchem.1c00019 · 被引用次数：29 · 研究领域：Cancer, Hypoxia, and Metabolism、Glioma Diagnosis and Treatment、Medical Imaging Techniques and Applications

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).