Pyrazolo[1,5-a]pyrimidine TRPC6 antagonists for the treatment of gastric cancer

Mingmin Ding, Hongbo Wang, Chunrong Qu, Fuchun Xu, Yingmin Zhu, Guangyao Lv, Yungang Lu, Qingjun Zhou, Hui Zhou, Xiaodong Zeng, Jingwen Zhang, Chunhong Yan, Jiacheng Lin, Huai Rong Luo, Zixing Deng, Yuling Xiao, Jinbin Tian, Michael X. Zhu, Xuechuan Hong

Research output: Contribution to journalArticlepeer-review

34 Scopus citations


Transient receptor potential canonical 6 (TRPC6) proteins form receptor-operated Ca2+-permeable channels, which have been thought to bring benefit to the treatment of diseases, including cancer. However, selective antagonists for TRPC channels are rare and none of them has been tested against gastric cancer. Compound 14a and analogs were synthesized by chemical elaboration of previously reported TRPC3/6/7 agonist 4o. 14a had very weak agonist activity at TRPC6 expressed in HEK293 cells but exhibited strong inhibition on both 4o-mediated and receptor-operated activation of TRPC6 with an IC50 of about 1 μM. When applied to the culture media, 14a suppressed proliferation of AGS and MKN45 cells with IC50 values of 17.1 ± 0.3 and 18.5 ± 1.0 μM, respectively, and inhibited tube formation and migration of cultured human endothelial cells. This anti-tumor effect on gastric cancer was further verified in xenograft models using nude mice. This study has found a new tool compound which shows excellent therapeutic potential against human gastric cancer most likely through targeting TRPC6 channels.

Original languageEnglish (US)
Pages (from-to)47-55
Number of pages9
JournalCancer Letters
StatePublished - Sep 28 2018
Externally publishedYes


  • Anticancer
  • Ca signaling
  • Drug discovery
  • Nonselective cation channels
  • TRPC channels

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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