GAP mimetic activity of pan-Ras TCI daraxonrasib synergizes with K-Ras Switch-II pocket inhibition

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Tricomplex inhibitors (TCIs) are a new class of direct Ras inhibitors targeting the GTP-bound Ras(on) state by recruiting Cyclophilin A.
• Daraxonrasib (RMC-6236), a pan-Ras TCI, restores GTPase activity in G12-mutant Ras proteins.
• Structural analysis reveals pan-Ras TCIs mimic endogenous GTPase-activating protein (GAP) complexes, acting as pharmacologic GAP mimetics.

Purpose of the Study:

• To investigate the synergistic potential of daraxonrasib with Switch-II pocket K-Ras inhibitors.
• To evaluate the combination's efficacy in enhancing Ras pathway inhibition and cellular viability.

Main Methods:

• Structural analysis of pan-Ras TCI bound to K-Ras(GDP-AlF3).
• Assessing daraxonrasib's ability to sensitize K-Ras(GTP) to adagrasib labeling in vitro and in cells.
• Evaluating combination therapy effects on p-ERK suppression and cell viability in K-Ras G12C and G12D mutant cell lines.

Main Results:

• Pan-Ras TCIs function as pharmacologic GAP mimetics by stabilizing a transition-state arrangement.
• Daraxonrasib sensitizes K-Ras(GTP) to adagrasib labeling, indicating enhanced inhibitor engagement.
• Combinations of daraxonrasib with adagrasib or HRS-4642 demonstrated rapid p-ERK suppression and significant synergistic effects on cell viability.

Conclusions:

• Pharmacologic GAP mimetics are rational and potent combination partners for Switch-II pocket inhibitors.
• Synergistic combinations can deepen and prolong pathway suppression, potentially reducing toxicity and overcoming resistance.
• This strategy offers a promising approach for enhanced cancer therapy by targeting Ras-mutated cancers.