Structure based discovery of clomifene as a potent inhibitor of cancer-associated mutant IDH1
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Mengzhu Zheng1,*, Weiguang Sun1,*, Suyu Gao2,*, Shanshan Luan1, Dan Li1, Renqi Chen3, Qian Zhang1, Lixia Chen2, Jiangeng Huang1 and Hua Li1,2
1Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
2Wuya College of Innovation, School of Traditional Chinese Materia Medica, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
3Department of Mathematics Computer Science, Emory College of Undergraduates, Emory University, Atlanta, GA 30322, USA
*These authors have contributed equally to this work
Hua Li, email: [email protected]
Jiangeng Huang, email: [email protected]
Lixia Chen, email: [email protected]
Keywords: IDH1, clomifene, virtual ligand screening, cancer, drug repurposing
Received: March 01, 2017 Accepted: April 11, 2017 Published: April 27, 2017
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.
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