The structure of KRAS^G12C bound to divarasib highlights features of potent switch-II pocket engagement

Area of Science:

• Oncology
• Structural Biology
• Medicinal Chemistry

Background:

• KRAS is a frequently mutated oncogene in cancer, with G12C mutations leading to hyperactivated MAPK signaling.
• Sotorasib and adagrasib are FDA-approved KRAS^G12C inhibitors, with ongoing efforts to develop more effective agents.
• Divarasib shows promise in clinical trials, demonstrating high response rates and specific KRAS^G12C inhibition.

Purpose of the Study:

• To determine the high-resolution crystal structure of KRAS-4B^G12C in complex with divarasib.
• To elucidate the structural details of divarasib's binding mechanism and compare it to existing inhibitors.
• To identify structural features that can inform the development of novel KRAS inhibitors.

Main Methods:

• High-resolution crystallography was employed to obtain the structure of the KRAS^G12C-divarasib complex.
• Structural analysis focused on the binding pocket, allosteric interactions, and conformational differences of the switch-II loop.
• Comparison of the divarasib-bound structure with existing structures of KRAS^G12C bound to other inhibitors.

Main Results:

• The crystal structure reveals divarasib binds to KRAS^G12C in the same allosteric pocket as sotorasib and adagrasib.
• Distinct conformations of the switch-II loop were observed, with differences up to 5.6 Å in Cα atom positions.
• Specific structural features of the divarasib complex were identified, differentiating its binding mode.

Conclusions:

• The distinct switch-II loop conformation in the divarasib-bound structure provides novel structural insights.
• These findings can guide future medicinal chemistry efforts for developing KRAS^G12C inhibitors with improved efficacy and specificity.
• Understanding these structural nuances is crucial for advancing targeted cancer therapies for KRAS-mutated cancers.