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Discovery of novel BET inhibitors by drug repurposing of nitroxoline and its analogues

文献类型：期刊论文

作者Jiang, Hao1,2; Xing, Jing1,2; Wang, Chen1,2; Zhang, Hao1; Yue, Liyan1; Wan, Xiaozhe1; Chen, Wei3; Ding, Hong1; Xie, Yiqian1; Tao, Hongru1
刊名ORGANIC & BIOMOLECULAR CHEMISTRY
出版日期2017-11-28
卷号15期号:44页码:9352-9361
ISSN号1477-0520
DOI10.1039/c7ob02369c
文献子类Article
英文摘要The BET family of bromodomain-containing proteins (BRDs) is believed to be a promising drug target for therapeutic intervention in a number of diseases including cancer, inflammation and cardiovascular diseases. Hence, there is a great demand for novel chemotypes of BET inhibitors. The drug repurposing strategy offers great benefits to find inhibitors with known safety and pharmacokinetic profiles, thus increasing medicinal chemists' interest in recent years. Using the drug repurposing strategy, a BRD4-specific score based virtual screening campaign on an in-house drug library was conducted followed by the ALPHA screen assay test. Nitroxoline, an FDA-approved antibiotic, was identified to effectively disrupt the interaction between the first bromodomain of BRD4 (bromodomain-containing protein 4) and acetylated H4 peptide with IC50 of 0.98 mu M. Nitroxoline inhibited all BET family members with good selectivity against non-BET bromodomain-containing proteins, thus it is defined as a selective BET inhibitor. Based on the crystal structure of the nitroxoline-BRD4_BD1 complex, the mechanism of action as well as BET specificity of nitroxoline were determined. Since the anticancer activity of nitroxoline against MLL leukemia, one of the BET related diseases, has not been studied before, we tested whether nitroxoline might serve as a potential repurposing drug candidate for MLL leukemia. Nitroxoline effectively inhibited the proliferation of MLL leukemia cells by inducing cell cycle arrest and apoptosis. The profound efficacy is, at least in part, due to the inhibition of BET and downregulation of target gene transcription. Our discovery of nitroxoline as a BET inhibitor suggests potential application of nitroxoline and its derivatives for clinical translation in BET family related diseases.
WOS关键词BROMODOMAIN PROTEIN BRD4 ; ACETYLATED HISTONE H4 ; P-TEFB ; STRUCTURAL BASIS ; IN-VITRO ; CANCER ; RECOGNITION ; OPTIMIZATION ; RECRUITMENT ; CANDIDATE
资助项目China Postdoctoral Science Foundation[2016 M590391] ; National Natural Science Foundation of China[21472208] ; National Natural Science Foundation of China[81625022] ; National Natural Science Foundation of China[81430084] ; National Natural Science Foundation of China[81773634] ; National Natural Science Foundation of China[21210003] ; National Natural Science Foundation of China[81230076] ; National Natural Science Foundation of China[81703415] ; Chinese Academy of Sciences[XDA12050201]
WOS研究方向Chemistry
语种英语
WOS记录号WOS:000415342200011
出版者ROYAL SOC CHEMISTRY
源URL[http://119.78.100.183/handle/2S10ELR8/272393]  
专题药物发现与设计中心
中科院受体结构与功能重点实验室
新药研究国家重点实验室
通讯作者Chen, Shijie; Zheng, Mingyue; Zhang, Yuanyuan
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China;
2.Univ Chinese Acad Sci, 19 Yuquan Rd, Beijing 100049, Peoples R China;
3.Shanghai Jiao Tong Univ, Sch Med, Renji Hosp, Dept Urol, 160 Pujian Rd, Shanghai 200127, Peoples R China;
4.ShanghaiTech Univ, Sch Life Sci & Technol, 100 Haike Rd, Shanghai 201210, Peoples R China;
5.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Jiang, Hao,Xing, Jing,Wang, Chen,et al. Discovery of novel BET inhibitors by drug repurposing of nitroxoline and its analogues[J]. ORGANIC & BIOMOLECULAR CHEMISTRY,2017,15(44):9352-9361.
APA Jiang, Hao.,Xing, Jing.,Wang, Chen.,Zhang, Hao.,Yue, Liyan.,...&Luo, Cheng.(2017).Discovery of novel BET inhibitors by drug repurposing of nitroxoline and its analogues.ORGANIC & BIOMOLECULAR CHEMISTRY,15(44),9352-9361.
MLA Jiang, Hao,et al."Discovery of novel BET inhibitors by drug repurposing of nitroxoline and its analogues".ORGANIC & BIOMOLECULAR CHEMISTRY 15.44(2017):9352-9361.

入库方式： OAI收割

来源：上海药物研究所

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