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

  • J Med Chem. 2019 Feb 14;62(3):1373-1384. doi: 10.1021/acs.jmedchem.8b01496.
Hao Chai  1  2 ,  Xi Cheng  1 ,  Bin Zhou  1  2 ,  Lifen Zhao  1 ,  Xianhua Lin  3 ,  Dongping Huang  3 ,  Weiqiang Lu  3 ,  Hao Lv  1  2 ,  Feng Tang  1 ,  Qiansen Zhang  3 ,  Wei Huang  1  2 ,  Yang Li  1  2 ,  Huaiyu Yang  3
Affiliations
  • 1. State Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica , Chinese Academy of Sciences , 555 Zuchongzhi Road , Shanghai 201203 , China.
  • 2. University of Chinese Academy of Sciences , No. 19A Yuquan Road , Beijing 100049 , China.
  • 3. Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences , East China Normal University , 500 Dongchuan Road , Shanghai 200241 , China.
PMID: 30620187 DOI: 10.1021/acs.jmedchem.8b01496
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.

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