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ID: ALA4422635
Journal: J Med Chem
Title: Structure-Based Discovery of a Subtype-Selective Inhibitor Targeting a Transient Receptor Potential Vanilloid Channel.
Authors: Chai H, Cheng X, Zhou B, Zhao L, Lin X, Huang D, Lu W, Lv H, Tang F, Zhang Q, Huang W, Li Y, Yang H.
Abstract: 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.
CiteXplore: 30620187