Structure-Based Discovery of a Subtype-Selective Inhibitor Targeting a Transient Receptor Potential Vanilloid Channel
Structure-Based Discovery of a Subtype-Selective Inhibitor Targeting a Transient Receptor Potential Vanilloid Channel
复制标题
基于结构的针对瞬时受体电位香草酸通道的亚型选择性抑制剂的发现
DOI：
10.1021/acs.jmedchem.8b01496
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发表时间：
2019
影响因子：
7.3
通讯作者：
Yang Huaiyu
中科院分区：
文献类型：
--
作者：
Chai Hao;Cheng Xi;Zhou Bin;Zhao Lifen;Lin Xianhua;Huang Dongping;Lu Weiqiang;Lv Hao;Tang Feng;Zhang Qiansen;Huang Wei;Li Yang;Yang Huaiyu
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.
