Journal of Medicinal Chemistry p. 4913 - 4946 (2021)
Update date:2022-07-30
Topics:
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.
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-2H-1λ2-quinoline-2,5(6H)-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).
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