Specific inhibition of oncogenic RAS using cell-permeable RAS-binding domains

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Oncogenic RAS proteins are key drivers in many human cancers.
• Targeting RAS is challenging due to its intracellular location and lack of druggable pockets.

Purpose of the Study:

• To develop a feasible strategy for designing RAS inhibitors using intracellular delivery of RAS-binding domain (RBD).
• To identify a cell-permeable pan-RAS inhibitor targeting various RAS mutants.

Main Methods:

• Screening of 51 combinations of RBD and cell-permeable peptides.
• Investigating the mechanism of action, including cell membrane crossing via endocytosis and RAS-effector interaction inhibition.
• Evaluating anticancer activity in KRAS-mutant cancer cell lines.
• Assessing target specificity using transcriptome and alanine mutation analyses.

Main Results:

• Identified Pen-cRaf-v1 as a cell-permeable pan-RAS inhibitor targeting both G12C and non-G12C RAS mutants.
• Pen-cRaf-v1 inhibits RAS-effector interaction and demonstrates anticancer activity.
• Pen-cRaf-v1 shows comparable activity to a leading pan-RAS inhibitor (BI-2852) with high target specificity.

Conclusions:

• Intracellular delivery of RBD is a feasible strategy for designing RAS inhibitors.
• Pen-cRaf-v1 represents a promising therapeutic candidate for RAS-mutant cancers.
• Specific inhibition of oncogenic RAS is achievable through this novel approach.