Portal de Periódicos da CAPES

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

2017; Impact Journals LLC; Volume: 8; Issue: 27 Linguagem: Inglês

10.18632/oncotarget.17464

1949-2553

Mengzhu Zheng, Weiguang Sun, Suyu Gao, Shanshan Luan, Dan Li, Renqi Chen, Qian Zhang, Lixia Chen, Jiangeng Huang, Hua Li,

Acute Myeloid Leukemia Research

// Mengzhu Zheng 1, * , Weiguang Sun 1, * , Suyu Gao 2, * , Shanshan Luan 1 , Dan Li 1 , Renqi Chen 3 , Qian Zhang 1 , Lixia Chen 2 , Jiangeng Huang 1 and Hua Li 1, 2 1 Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China 2 Wuya 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 3 Department of Mathematics Computer Science, Emory College of Undergraduates, Emory University, Atlanta, GA 30322, USA * These authors have contributed equally to this work Correspondence to: Hua Li, email: li_hua@hust.edu.cn Jiangeng Huang, email: jiangenghuang@hust.edu.cn Lixia Chen, email: syzyclx@163.com Keywords: IDH1, clomifene, virtual ligand screening, cancer, drug repurposing Received: March 01, 2017 Accepted: April 11, 2017 Published: April 27, 2017 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.