Mutant-Specific Targeting of Ras G12C Activity by Covalently Reacting Small Molecules.

Area of Science:

• Oncology
• Molecular Biology
• Medicinal Chemistry

Background:

• KRAS G12C is an oncogenic mutation driving various cancers.
• Targeting KRAS G12C has been a significant challenge in cancer therapy.
• Covalent inhibitors offer a promising strategy for KRAS G12C targeting.

Purpose of the Study:

• To review and compare recently developed covalent molecules targeting KRAS G12C.
• To evaluate the physico-chemical principles of different inhibitor classes.
• To propose a novel therapeutic approach for KRAS G12C-driven cancers.

Main Methods:

• Comparative analysis of two distinct classes of KRAS G12C inhibitors.
• Evaluation of reversible switch-II pocket (S-IIP) interacting compounds.
• Assessment of GDP/GTP binding site competing molecules.

Main Results:

• Both inhibitor classes effectively lock KRAS G12C in an inactive GDP-bound state.
• GDP/GTP competing molecules require careful consideration of guanine nucleotide exchange factors (GEFs).
• GEF activity is elevated in cells with activated Ras mutants, impacting inhibitor efficacy.

Conclusions:

• Covalent inhibitors targeting KRAS G12C represent a significant advancement in oncology.
• A novel approach using GEF-independent guanine binding site inhibitors is proposed.
• This strategy may overcome limitations associated with GEF interactions in KRAS G12C therapy.