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

• Type of Material: Article
• Authors: Mengzhu Zheng, Huazhong University of Science & Technology; Weiguang Sun, Huazhong University of Science & Technology; Suyu Gao, Shenyang Pharmaceutical University; Shanshan Luan, Huazhong University of Science & Technology; Dan Li, Huazhong University of Science & Technology; Renqi Chen, Emory University; Qian Zhang, Emory University; Lixia Chen, Shenyang Pharmaceutical University; Jiangeng Huang, Huazhong University of Science & Technology; Hua Li, Huazhong University of Science & Technology
• Language: English
• Date: 2017-07-04
• Publisher: Impact Journals LLC
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © Zheng et al. 2017.
• License: Creative Commons Attribution 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.18632/oncotarget.17464
• Title of Journal or Parent Work: Oncotarget
• Volume: 8
• Issue: 27
• Start Page: 44255
• End Page: 44265
• Grant/Funding Information: We acknowledge support from the Fundamental Research Funds for the Central Universities [grant numbers HUST-2015TS130].
• Keywords: Selective inhibition; Science & Technology; Life Sciences & Biomedicine; cancer; Cell Biology; clomifene; Docking; drug repurposing; virtual ligand screening; Differentiation; Oncology; IDH1; Growth
• Research Categories: Education, Mathematics; Chemistry, Biochemistry; Health Sciences, Oncology; Health Sciences, Pharmacy; Biology, Cell

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.