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Structure based discovery of clomifene as a potent inhibitor of cancer-associated mutant IDH1.


ABSTRACT: Isocitrate dehydrogenase (IDH) plays an indispensable role in the tricarboxylic acid cycle, and IDH mutations are present in nearly 75% of glioma and 20% of acute myeloid leukemia. One IDH1R132H inhibitor (clomifene citrate) was found by virtual screening method, which can selectively suppress mutant enzyme activities in vitro and in vivo with a dose-dependent manner. The molecular docking indicated that clomifene occupied the allosteric site of the mutant IDH1. Enzymatic kinetics also demonstrated that clomifene inhibited mutant enzyme in a non-competitive manner. Moreover, knockdown of mutant IDH1 in HT1080 cells decreased the sensitivity to clomifene. In vivo studies indicated that clomifene significantly suppressed the tumor growth of HT1080-bearing CB-17/Icr-scid mice with oral administration of 100 mg/kg and 50 mg/kg per day. In short, our findings highlight clomifene may have clinical potential in tumor therapies as a safe and effective inhibitor of mutant IDH1.

SUBMITTER: Zheng M 

PROVIDER: S-EPMC5546478 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Structure based discovery of clomifene as a potent inhibitor of cancer-associated mutant IDH1.

Zheng Mengzhu M   Sun Weiguang W   Gao Suyu S   Luan Shanshan S   Li Dan D   Chen Renqi R   Zhang Qian Q   Chen Lixia L   Huang Jiangeng J   Li Hua H  

Oncotarget 20170701 27


Isocitrate dehydrogenase (IDH) plays an indispensable role in the tricarboxylic acid cycle, and IDH mutations are present in nearly 75% of glioma and 20% of acute myeloid leukemia. One IDH1R132H inhibitor (clomifene citrate) was found by virtual screening method, which can selectively suppress mutant enzyme activities in vitro and in vivo with a dose-dependent manner. The molecular docking indicated that clomifene occupied the allosteric site of the mutant IDH1. Enzymatic kinetics also demonstra  ...[more]

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