| Literature DB >> 33822623 |
Jason M Rohde1, Surendra Karavadhi1, Rajan Pragani1, Li Liu1, Yuhong Fang1, Weihe Zhang2, Andrew McIver2, Hongchao Zheng2, Qingyang Liu2, Mindy I Davis1, Daniel J Urban1, Tobie D Lee1, Dorian M Cheff1, Melinda Hollingshead3, Mark J Henderson1, Natalia J Martinez1, Kyle R Brimacombe1, Adam Yasgar1, Wei Zhao1, Carleen Klumpp-Thomas1, Sam Michael1, Joseph Covey4, William J Moore5, Gordon M Stott5, Zhuyin Li1, Anton Simeonov1, Ajit Jadhav1, Stephen Frye2, Matthew D Hall1, Min Shen1, Xiaodong Wang2, Samarjit Patnaik1, Matthew B Boxer1.
Abstract
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).Entities:
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Year: 2021 PMID： 33822623 PMCID： PMC8968748 DOI： 10.1021/acs.jmedchem.1c00019
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446