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

Abstract Tricomplex inhibitors (TCIs) are a novel class of direct Ras inhibitors that target the GTP-bound Ras(on) state trough recruitment of Cyclophilin A. Daraxonrasib (RMC-6236) is a pan-Ras TCI that was recently shown to restore GTPase activity of G12-mutant Ras proteins. Structural analysis of a pan-Ras TCI bound to K-Ras(GDP– AlF3) reveals a transition-state arrangement of Tyr32 and Gln61 that closely resembles endogenous GTPase– GAP complexes. This includes a closed Switch-I conformation engaging the cis-GTPase machinery in a manner analogous to non-arginine-finger GAPs such as RanGAP. These observations position pan-Ras TCIs as pharmacologic GAP mimetics. The GTPase-promoting activity of daraxonrasib suggests synergy with Switch-II pocket K-Ras inhibitors, including the approved GDP-state selective K-Ras G12C inhibitor adagrasib (MRTX-849), whose engagement of K-Ras(GTP) is kinetically constrained by slow endogenous hydrolysis of the mutant GTPase. We demonstrate that daraxonrasib sensitizes K-Ras(GTP) to adagrasib labeling in both recombinant protein and cellular context. In K-Ras G12C and G12D mutant cell lines, combinations of daraxonrasib with adagrasib or HRS-4642 (MRTX-1133 analog) yield more rapid K-Ras engagement, rapid p-ERK suppression, and significant Loewe synergy scores in viability assays. These findings establish GAP mimetics as rational and potent combination partners for SW-II inhibitors. The synergistic combination has potential to deepen and prolong pathway suppression while enabling dose reductions that may mitigate on-target toxicity and resistance.