Computationally Empowered Workflow Identifies Novel Covalent Allosteric Binders for KRAS^G12C

Area of Science:

• Oncology
• Medicinal Chemistry
• Computational Drug Discovery

Background:

• KRAS mutations are common in lethal cancers, making it a key target for anticancer drugs.
• The KRAS G12C mutation presents a druggable allosteric binding site, driving significant research interest.

Purpose of the Study:

• To identify novel and selective covalent inhibitors targeting the KRAS G12C mutation using a computational approach.
• To explore new chemical scaffolds and binding modes for KRAS G12C inhibition.

Main Methods:

• Virtual screening of molecules using pharmacophore modeling and docking.
• Prioritization of compounds via free-energy perturbation calculations.
• Synthesis and structure-activity relationship (SAR) studies of identified inhibitors.
• Molecular dynamics simulations and X-ray crystallography for binding mode analysis.

Main Results:

• A novel naphthyridinone scaffold was identified with potent KRAS G12C inhibitory activity.
• Structure-activity relationship studies guided the optimization of inhibitor potency.
• Crystallization revealed an unprecedented binding mode of the inhibitor to KRAS G12C.

Conclusions:

• The computational strategy successfully identified novel covalent KRAS G12C inhibitors.
• The discovered naphthyridinone scaffold and its binding mode offer new avenues for KRAS-targeted cancer therapy.
• This work advances the development of targeted therapies for KRAS-mutated cancers.