KRAS G12C fragment screening renders new binding pockets.

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• KRAS genes are frequently mutated oncogenes in various cancers, with the G12C mutation contributing significantly to cancer mortality.
• Despite decades of research and drug development efforts targeting KRAS, no KRAS-specific drugs have been approved until recently.
• Emerging covalent inhibitors like MRTX849 and Sotorasib target the KRAS G12C mutation by binding to Cysteine 12.

Purpose of the Study:

• To identify novel binding pockets on the KRAS G12C protein surface.
• To explore new therapeutic strategies for KRAS G12C-driven cancers through fragment screening.

Main Methods:

• Conducted two fragment screening drug discovery campaigns.
• One campaign focused on identifying non-covalent binders to KRAS G12C.
• The other campaign focused on identifying covalent binders to KRAS G12C.

Main Results:

• Identified previously undescribed binding pockets on the KRAS G12C protein surface.
• The fragment screening campaigns yielded insights into potential new drug targets on KRAS G12C.
• These new pockets offer alternative sites for therapeutic intervention beyond the Switch II pocket.

Conclusions:

• The identification of novel binding pockets on KRAS G12C presents new opportunities for drug development.
• Fragment screening provides a valuable approach for discovering new therapeutic strategies against KRAS G12C.
• These findings could pave the way for more effective treatments for lung, colorectal, and pancreatic cancers harboring the KRAS G12C mutation.