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

• Published in: Journal of medicinal chemistry Vol. 64; no. 8; pp. 4913 - 4946
• Main Authors: Rohde, Jason M, Karavadhi, Surendra, Pragani, Rajan, Liu, Li, Fang, Yuhong, Zhang, Weihe, McIver, Andrew, Zheng, Hongchao, Liu, Qingyang, Davis, Mindy I, Urban, Daniel J, Lee, Tobie D, Cheff, Dorian M, Hollingshead, Melinda, Henderson, Mark J, Martinez, Natalia J, Brimacombe, Kyle R, Yasgar, Adam, Zhao, Wei, Klumpp-Thomas, Carleen, Michael, Sam, Covey, Joseph, Moore, William J, Stott, Gordon M, Li, Zhuyin, Simeonov, Anton, Jadhav, Ajit, Frye, Stephen, Hall, Matthew D, Shen, Min, Wang, Xiaodong, Patnaik, Samarjit, Boxer, Matthew B
• Format: Journal Article
• Language: English
• Published: United States 22.04.2021
• Subjects: Animals; Brain - metabolism; Cell Line, Tumor; Drug Evaluation, Preclinical; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - therapeutic use; Female; Glycine - analogs & derivatives; Glycine - therapeutic use; Half-Life; Humans; Isocitrate Dehydrogenase - antagonists & inhibitors; Isocitrate Dehydrogenase - genetics; Isocitrate Dehydrogenase - metabolism; Mice; Mice, Nude; Microsomes, Liver - metabolism; Mutagenesis, Site-Directed; Neoplasms - drug therapy; Neoplasms - pathology; Pyridines - therapeutic use; Pyridones - chemistry; Pyridones - metabolism; Pyridones - therapeutic use; Rats; Structure-Activity Relationship; Xenograft Model Antitumor Assays
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.1c00019

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 -1λ -quinoline-2,5(6 )-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 ( - , ). 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, showed higher tumoral concentrations that corresponded to lower 2-HG concentrations, when compared with the approved drug AG-120 (ivosidenib).