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


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).

SUBMITTER: Rohde JM 

PROVIDER: S-EPMC8968748 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Discovery and Optimization of 2<i>H</i>-1λ<sup>2</sup>-Pyridin-2-one Inhibitors of Mutant Isocitrate Dehydrogenase 1 for the Treatment of Cancer.

Rohde Jason M JM   Karavadhi Surendra S   Pragani Rajan R   Liu Li L   Fang Yuhong Y   Zhang Weihe W   McIver Andrew A   Zheng Hongchao H   Liu Qingyang Q   Davis Mindy I MI   Urban Daniel J DJ   Lee Tobie D TD   Cheff Dorian M DM   Hollingshead Melinda M   Henderson Mark J MJ   Martinez Natalia J NJ   Brimacombe Kyle R KR   Yasgar Adam A   Zhao Wei W   Klumpp-Thomas Carleen C   Michael Sam S   Covey Joseph J   Moore William J WJ   Stott Gordon M GM   Li Zhuyin Z   Simeonov Anton A   Jadhav Ajit A   Frye Stephen S   Hall Matthew D MD   Shen Min M   Wang Xiaodong X   Patnaik Samarjit S   Boxer Matthew B MB  

Journal of medicinal chemistry 20210406 8


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<i>H</i>-1λ<sup>2</sup>-quinoline-2,5(6<i>H</i>)-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 <b>(+)-119</b  ...[more]

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