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Thiazole peptidomimetics as chemical modulators of KRAS gene expression via G-quadruplex stabilization

Debasmita Biswas1, Ananta Gorai1, Sandip Maiti1

  • 1School of Chemical Sciences, Indian Association for the Cultivation of Science Kolkata 700032 India ocjd@iacs.res.in https://iacs.res.in/athusers/index.php?navid=0&userid=IACS0034#219524.

RSC Chemical Biology
|October 16, 2025
PubMed

Insights

Researchers developed novel peptidomimetics targeting KRAS G-quadruplex DNA. TTh2 selectively binds and stabilizes the KRAS G-quadruplex, downregulating oncogene expression and inhibiting cancer cell pathways.

Area of Science:

  • Medicinal Chemistry
  • Molecular Biology
  • Cancer Research

Background:

  • KRAS is a frequently mutated oncogene in human cancers, posing a therapeutic challenge.
  • Targeting KRAS has been difficult, with the oncogene often considered
  • undruggable
  • .

Purpose of the Study:

  • To synthesize and evaluate novel triazole-containing peptidomimetics for selective DNA G-quadruplex interactions.
  • To investigate the potential of these compounds in modulating oncogene expression and downstream signaling pathways.

Main Methods:

  • Synthesis of triazole-containing peptidomimetics (TTh1 and TTh2).
  • Biophysical studies to assess DNA G-quadruplex binding and stabilization.
  • Analysis of KRAS mRNA and protein levels in HeLa cells.
  • Evaluation of downstream signaling pathway inhibition (MAPK, Akt/mTOR).

Main Results:

  • TTh2 selectively binds to and stabilizes the KRAS G-quadruplex structure.
  • TTh2 treatment resulted in significant suppression of KRAS mRNA and protein levels.
  • Downregulation of KRAS correlated with inhibition of MAPK and Akt/mTOR signaling pathways.
  • These pathways are critical for cancer cell proliferation and survival.

Conclusions:

  • G-quadruplex binding peptidomimetics show potential as therapeutic agents.
  • Selective stabilization of promoter G-quadruplex structures can modulate oncogene expression.
  • TTh2 represents a promising chemical tool for targeting KRAS-driven cancers.

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