Direct inhibition of oncogenic KRAS by hydrocarbon-stapled SOS1 helices

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Activating mutations in Kirsten rat sarcoma viral oncogene homolog (KRAS) are implicated in ~30% of human cancers, contributing to tumor development and chemoresistance.
• Targeting diverse KRAS mutants with high-affinity inhibitors presents a significant therapeutic challenge in oncology.

Purpose of the Study:

• To develop and validate stabilized alpha helices of son of sevenless 1 (SAH-SOS1) peptides as direct inhibitors of wild-type and mutant KRAS.
• To investigate the therapeutic potential of SAH-SOS1 peptides in KRAS-driven cancers.

Main Methods:

• SAH-SOS1 peptides were designed to bind sequence-specifically to KRAS and its mutants.
• Functional assays assessed KRAS nucleotide binding inhibition and SAH-SOS1 peptide cytotoxicity in cancer cells.
• Mechanism of action was elucidated by analyzing ERK-MAP kinase signaling pathway modulation in cancer cells and a Drosophila melanogaster model.

Main Results:

• SAH-SOS1 peptides demonstrated sequence-specific binding to wild-type and mutant KRAS, dose-responsively blocking nucleotide association.
• Functional binding correlated with SAH-SOS1-induced cytotoxicity in cancer cells harboring KRAS mutations.
• SAH-SOS1 peptides effectively down-regulated the ERK-MAP kinase signaling cascade in KRAS-driven cancer models.

Conclusions:

• SAH-SOS1 peptides represent a novel class of therapeutics capable of directly inhibiting both wild-type and mutant KRAS.
• These findings support the potential utility of SAH-SOS1 peptides for neutralizing oncogenic KRAS and treating associated human cancers.