What question did this study set out to answer?

To evaluate the collaboration between GAP mimetics and K-Ras Switch-II inhibitors in targeting mutant K-Ras.

March 7, 2026

Abstract A016: GAP mimetics display synergy with K-Ras Switch-II inhibition

Key Points

To evaluate the collaboration between GAP mimetics and K-Ras Switch-II inhibitors in targeting mutant K-Ras.
Analyzed the structural interaction of daraxonrasib with K-Ras
Conducted viability assays in K-Ras G12C and G12D mutant cell lines
Assessed the kinetic engagement and GTPase-promoting activity of daraxonrasib
Evaluated synergy scores with various inhibitor combinations.
Daraxonrasib was found to enhance the sensitivity of K-Ras(GTP) G12C to adagrasib labeling
Combination treatments showed accelerated K-Ras engagement and rapid p-ERK suppression
Significant Loewe synergy scores were observed in viability assays
GAP mimetics demonstrated potential to improve treatment efficacy while reducing toxicity.

Abstract

Abstract Tricomplex inhibitors (TCIs) represent a new class of direct Ras inhibitors that engage the active, GTP-loaded Ras (on) state through recruitment of Cyclophilin A. Daraxonrasib (RMC-6236) is a pan-Ras TCI which has been recently reported to restore intrinsic GTPase activity of G12-mutant Ras isoforms. Structural analysis of a pan-Ras TCI bound to K-Ras (GDP–AlF3) reveals a transition-state arrangement of Tyr32 and Gln61 that closely mirrors 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 engagement of K-Ras (GTP) by first generation Switch-II pocket K-Ras inhibitors, including the approved GDP-state selective K-Ras G12C inhibitor adagrasib (MRTX-849), is kinetically constrained by slow endogenous hydrolysis of the mutant GTPase. The GTPase-promoting activity of daraxonrasib therefore suggests synergy with adagrasib and other Switch-II pocket inhibitors by enriching the more sensitive GDP-state. We demonstrate that daraxonrasib sensitizes K-Ras (GTP) G12C to covalent 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 accelerated 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. Citation Format: Patrick Pfaff, Kevan Shokat. GAP mimetics display synergy with K-Ras Switch-II inhibition abstract. In: Proceedings of the AACR Special Conference in Cancer Research: RAS Oncogenesis and Therapeutics; 2026 Mar 5-8; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (5Suppl₁): Abstract nr A016.

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Cite This Study

Pfaff et al. (Thu,) studied this question.

synapsesocial.com/papers/69abc1955af8044f7a4ea558 https://doi.org/https://doi.org/10.1158/1538-7445.rasoncother26-a016

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