Abstract ND06: Discovery of RMC-5127, an oral, RAS (ON) G12V-selective, noncovalent, tri-complex inhibitor

The RAS G12V mutation is among the most common oncogenic drivers in pancreatic, colorectal, and non-small cell lung cancers. Within a tumor cell, RAS G12V exists predominantly in the active, GTP-bound (“RAS(ON)”) state leading to excessive downstream oncogenic signaling. The intrinsic GTP hydrolysis rate of RAS G12V is about 12-fold lower than that of KRAS G12C, biasing the cellular RAS G12V pool to the ON state and emphasizing the importance of targeting RAS G12V(ON) for maximal suppression of this oncogenic driver. Additionally, achieving selectivity for RAS G12V over wild-type RAS has, to date, been extremely challenging using conventional small molecules because the Val-12 residue is neither amenable to covalent inhibition nor to formation of polar, noncovalent interactions.The investigational agent RMC-5127 is a potent, orally bioavailable, RAS (ON) G12V-selective, noncovalent tri-complex inhibitor. In KRAS G12V mutant cancer cells, RMC-5127 forms a tri-complex between KRAS G12V(ON) and cyclophilin A (CypA), driving near-immediate disruption of RAS effector binding through steric occlusion and extinction of KRAS G12V(ON) signaling.RMC-5127 suppressed ERK phosphorylation and cell growth in multiple human KRAS G12V-addicted cancer cell lines in vitro, and a single dose induced dose-dependent, deep, and durable suppression of RAS pathway activation in vivo in subcutaneous xenograft models of KRAS G12V mutant cancers in mice. Across a panel of preclinical PDAC and NSCLC models harboring KRAS G12V, RMC-5127 monotherapy induced tumor regressions in the majority of models and was well-tolerated. In addition, dose-dependent exposure of RMC-5127 was observed in the whole brain of naïve mice, indicating the compound is brain penetrant, and RMC-5127 exhibited profound antitumor activity in relevant intracranial KRAS G12V mutant tumor xenograft models, with regressions observed at well-tolerated doses. Citation Format: Anne Edwards. Discovery of RMC-5127, an oral, RAS (ON) G12V-selective, noncovalent, tri-complex inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited s); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2): nr ND06.