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

doi:10.1021/acs.jmedchem.8b01496

	Structure-Based Discovery of a Subtype-Selective Inhibitor Targeting a Transient Receptor Potential Vanilloid Channel
	Chai, Hao 1,2,5; Cheng, Xi 1,2; Zhou, Bin 1,2,5; Zhao, Lifen 1,2; Lin, Xianhua 3,4; Huang, Dongping 3,4; Lu, Weiqiang 3,4; Lv, Hao 1,2,5; Tang, Feng 1,2; Zhang, Qiansen 3,4
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	2019-02-14
卷号	62 期号:3 页码:1373-1384
ISSN号	0022-2623
DOI	10.1021/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.
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关键词	LYSOPHOSPHATIDIC ACID ; TRPV1 STRUCTURES ; CELL-MIGRATION ; ACTIVATION ; AUTOTAXIN ; MECHANISMS ; TRANSITION ; EFFICIENT ; DYNAMICS ; DOCKING
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000459223600019
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/290443]
专题	中国科学院上海药物研究所
通讯作者	Huang, Wei; Li, Yang; Yang, Huaiyu
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 3.East China Normal Univ, Shanghai Key Lab Regulatory Biol, Inst Biomed Sci, 500 Dongchuan Rd, Shanghai 200241, Peoples R China 4.East China Normal Univ, Sch Life 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.