Fragment Optimization of Reversible Binding to the Switch II Pocket on KRAS Leads to a Potent, In Vivo Active...

Area of Science:

• Oncology
• Medicinal Chemistry
• Molecular Biology

Background:

• Activating KRAS mutations are common in cancer.
• The KRAS^G12C mutation presents a target for inhibitors due to cysteine at position 12.
• Current KRAS^G12C inhibitors are developed via covalent binding first.

Purpose of the Study:

• To discover a novel in vivo active KRAS^G12C inhibitor.
• To explore an alternative drug discovery approach for KRAS^G12C inhibitors.
• To provide a foundation for developing inhibitors against other KRAS mutants.

Main Methods:

• Structure-based drug design.
• Identification of reversible switch II pocket binders.
• Optimization for non-covalent binding followed by covalent warhead attachment.

Main Results:

• Discovery of the in vivo active KRAS^G12C inhibitor BI-0474.
• Successful application of a non-covalent to covalent binding strategy.
• Demonstration of an alternative approach to KRAS^G12C inhibitor development.

Conclusions:

• A novel strategy for discovering KRAS^G12C inhibitors has been established.
• The BI-0474 inhibitor is active in vivo.
• This approach can be extended to target other oncogenic KRAS mutations.