RMC-4998 is an orally available KRASG12C mutant inhibitor that targets the active or GTP-bound state of the KRASG12C mutant and binds to intracellular CYPA to form a triple complex to inhibit the ERK signaling pathway and induce apoptosis, which is of great significance for tumor research.

KRASG12C-GTP:1–10  nM

RMC-4998 is a selective KRASG12C inhibitor that forms a ternary complex with cyclophilin A and KRASG12C-GTP, enabling rapid covalent modification and inhibition of KRASG12C (IC₅₀ = 1–10 nM). RMC-4998 disrupts KRAS interactions with downstream effectors such as CRAF and SOS, effectively suppressing ERK signaling. RMC-4998 remains active even under RTK stimulation (e.g., EGF or HGF) and shows no activity against wild-type KRAS, NRAS, or HRAS[1].

In H358 xenograft mouse models, oral administration of RMC-4998 significantly inhibited tumor growth or induced regression, accompanied by ERK pathway suppression and apoptosis induction[1]. In KRASG12C-mutant NSCLC xenograft models (such as H2122, H2030, and multiple PDX models), oral administration of RMC-4998 (80 mg/kg, once daily) delayed tumor growth, while combination with the mTORC1 inhibitor RMC-6272 (6 mg/kg, intraperitoneally, once weekly) induced deep and durable complete tumor regressions without notable weight loss or hyperglycemia-related toxicity[2].