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

Mingmin Ding1, Hongbo Wang2, Chunrong Qu1

  • 1State Key Laboratory of Virology, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (MOE), Medical College, Tibet University, Lasa, China; Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals, Wuhan University School of Pharmaceutical Sciences, Wuhan, China.

Cancer Letters
|June 4, 2018
PubMed

Insights

A novel compound, 14a, effectively inhibits gastric cancer cell growth by targeting Transient Receptor Potential Canonical 6 (TRPC6) channels. This discovery offers a promising new therapeutic strategy for gastric cancer treatment.

Area of Science:

  • Pharmacology
  • Oncology
  • Molecular Biology

Background:

  • Transient Receptor Potential Canonical 6 (TRPC6) channels are implicated in various diseases, including cancer.
  • Selective TRPC6 antagonists are scarce, and their potential in gastric cancer treatment remains unexplored.

Purpose of the Study:

  • To synthesize and evaluate novel TRPC6 antagonists for their anti-cancer effects, specifically against gastric cancer.
  • To investigate the therapeutic potential of compound 14a and its analogs in preclinical models.

Main Methods:

  • Synthesis of compound 14a and analogs based on a known TRPC3/6/7 agonist.
  • In vitro assays using HEK293 cells to assess TRPC6 channel activity and inhibition.
  • Cell proliferation, tube formation, and migration assays using gastric cancer cell lines (AGS, MKN45) and human endothelial cells.
  • In vivo studies using xenograft models in nude mice to evaluate anti-tumor efficacy.

Main Results:

  • Compound 14a demonstrated potent inhibition of TRPC6 channel activation with an IC50 of approximately 1 μM.
  • 14a significantly suppressed proliferation of AGS and MKN45 gastric cancer cells (IC50 values ~17-18 μM).
  • Compound 14a inhibited endothelial cell tube formation and migration, and showed anti-tumor effects in vivo.

Conclusions:

  • Compound 14a is a potent TRPC6 channel inhibitor with significant anti-gastric cancer activity.
  • Targeting TRPC6 channels represents a promising therapeutic strategy for human gastric cancer.
  • Compound 14a serves as a valuable tool compound for further research in gastric cancer therapy.
Keywords:
AnticancerCa(2+) signalingDrug discoveryNonselective cation channelsTRPC channels

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