SOS1-inspired hydrocarbon-stapled peptide as a pan-Ras inhibitor

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Blocking the Ras-Son of Sevenless homolog 1 (SOS1) interaction is a key strategy for cancers with oncogenic Ras mutations.
• K-Ras mutations are prevalent (86%) in Ras-driven cancers, followed by N-Ras (11%) and H-Ras (3%).

Purpose of the Study:

• To design and synthesize hydrocarbon-stapled peptides as pan-Ras inhibitors.
• To evaluate the efficacy of these peptides in inhibiting cancer cell proliferation and inducing apoptosis.

Main Methods:

• Synthesis of hydrocarbon-stapled peptides to mimic the SOS1 alpha-helix.
• Structural modeling analysis to validate binding affinity and mechanism.
• In vitro assays to assess cancer cell proliferation inhibition and apoptosis induction.

Main Results:

• SSOSH-5 demonstrated a constrained alpha-helical structure and high-affinity binding to H-Ras.
• SSOSH-5 effectively inhibited proliferation and induced apoptosis in pan-Ras-mutated cancer cells dose-dependently.
• SSOSH-5 showed excellent cell membrane permeability and proteolytic resistance.

Conclusions:

• Peptide stapling is a viable strategy for developing peptide-based pan-Ras inhibitors.
• SSOSH-5 is a promising candidate for further development in treating Ras-driven cancers.