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Structure-Based Discovery of a Subtype-Selective Inhibitor Targeting a Transient Receptor Potential Vanilloid Channel

文献类型：期刊论文

作者Chai, Hao2,3,5; Cheng, Xi2,3; Zhou, Bin2,3,5; Zhao, Lifen2,3; Lin, Xianhua1,4; Huang, Dongping1,4; Lu, Weiqiang1,4; Lv, Hao2,3,5; Tang, Feng2,3; Zhang, Qiansen1,4
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2019-02-14
卷号62期号:3页码:1373-1384
ISSN号0022-2623
DOI10.1021/acs.jmedchem.8b01496
通讯作者Huang, Wei(huangwei@simm.ac.cn) ; Li, Yang(liyang@simm.ac.cn) ; Yang, Huaiyu(hyyang@bio.ecnu.edu.cn)
英文摘要Discovery of potent selective inhibitors targeting a protein from a highly conserved family is challenging. Using a strategy combining structural and evolutionary information, we discovered transient receptor potential (TRP) subtype-selective inhibitors (transient receptor potential vanilloid type 2 (TRPV2) inhibitors). We unveiled three ligand-binding sites of TRPV2 and compounds that bind to these sites. Structural optimization of the best-hit compound provided a potent selective TRPV2 inhibitor, SET2. The molecular basis and subtype-selective inhibition mechanism were quantitatively characterized and experimentally verified. Then, as an effective chemical probe, SET2 was used to investigate the function role of TRPV2. SET2-induced inhibition of TRPV2 reduced prostate cancer migration, which indicated TRPV2 as an antimetastasis therapeutic target. In addition, functional assays suggested that TRPV2 was coupled to a validated metastasis mediator, LPAR1. The discovery of the potent selective inhibitor potentially leads to novel avenues for pharmacological applications and therapeutic development targeting the TRPV2 channel.
WOS关键词LYSOPHOSPHATIDIC ACID ; TRPV1 STRUCTURES ; CELL-MIGRATION ; ACTIVATION ; AUTOTAXIN ; MECHANISMS ; TRANSITION ; EFFICIENT ; DYNAMICS ; DOCKING
资助项目National Science & Technology Major Project Key New Drug Creation and Manufacturing Program of China[2018ZX09711002] ; National Natural Science Foundation of China[21422208] ; National Natural Science Foundation of China[31671049] ; National Natural Science Foundation of China[31371066] ; E-Institutes of Shanghai Municipal Education Commission[E09013] ; Special Program for Applied Research on Super Computation of the NSFC-Guangdong Joint Fund[U1501501] ; State Key Laboratory of Bioorganic and Natural Products Chemistry
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000459223600019
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/290443]  
专题新药研究国家重点实验室
通讯作者Huang, Wei; Li, Yang; Yang, Huaiyu
作者单位1.East China Normal Univ, Sch Life Sci, 500 Dongchuan Rd, Shanghai 200241, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
4.East China Normal Univ, Shanghai Key Lab Regulatory Biol, Inst Biomed Sci, 500 Dongchuan Rd, Shanghai 200241, Peoples R China
5.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China
推荐引用方式
GB/T 7714		 Chai, Hao,Cheng, Xi,Zhou, Bin,et al. Structure-Based Discovery of a Subtype-Selective Inhibitor Targeting a Transient Receptor Potential Vanilloid Channel[J]. JOURNAL OF MEDICINAL CHEMISTRY,2019,62(3):1373-1384.
APA Chai, Hao.,Cheng, Xi.,Zhou, Bin.,Zhao, Lifen.,Lin, Xianhua.,...&Yang, Huaiyu.(2019).Structure-Based Discovery of a Subtype-Selective Inhibitor Targeting a Transient Receptor Potential Vanilloid Channel.JOURNAL OF MEDICINAL CHEMISTRY,62(3),1373-1384.
MLA Chai, Hao,et al."Structure-Based Discovery of a Subtype-Selective Inhibitor Targeting a Transient Receptor Potential Vanilloid Channel".JOURNAL OF MEDICINAL CHEMISTRY 62.3(2019):1373-1384.

入库方式： OAI收割

来源：上海药物研究所

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