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DIRAS3-derived cyclic peptides disrupt KRAS-RAF interaction and KRAS nanoclustering, suppressing KRAS-driven

Joshua P Gray1, Gamze Bildik1, Ha-Neul Kim2

  • 1Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.

Iscience
|November 17, 2025
PubMed

Insights

New cyclic peptides derived from DIRAS3 effectively inhibit KRAS signaling. These peptides show promise for treating KRAS-driven pancreatic ductal adenocarcinoma and low-grade serous ovarian cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Mutations in KRAS are key drivers in pancreatic ductal adenocarcinoma (PDAC) and low-grade serous ovarian cancer (LGSOC).
  • DIRAS3 protein disrupts RAS clustering and downstream signaling by binding to RAS proteins.

Purpose of the Study:

  • To develop and characterize novel DIRAS3-derived cyclic peptides as inhibitors of oncogenic KRAS.
  • To evaluate the efficacy of these peptides in preclinical models of PDAC and LGSOC.

Main Methods:

  • Conformationally constrained DIRAS3-derived peptides were synthesized using cyclization strategies.
  • Peptide characterization involved NMR and biolayer interferometry.
  • Inhibition of KRAS-BRAF interaction and KRAS nanoclustering was assessed.
  • Cell viability and tumor growth were evaluated in cell culture and xenograft models.

Main Results:

  • Cyclic peptides were successfully developed and characterized.
  • These peptides effectively attenuated KRAS-BRAF interaction and inhibited KRAS nanoclustering.
  • The peptides demonstrated efficient cell penetration and reduced cell viability.
  • Significant suppression of PDAC and LGSOC growth was observed in preclinical models.

Conclusions:

  • DIRAS3-based cyclic peptides offer a novel therapeutic strategy targeting oncogenic KRAS.
  • These peptides show potential for the treatment of KRAS-driven cancers, including PDAC and LGSOC.
  • The findings provide a promising framework for future drug development in oncology.
Keywords:
cancermolecular biologystructural biology

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