RM-041

RM-041 is a selective, orally bioavailable KRASG13C(ON) inhibitor that forms a covalent complex with KRASG13C(ON) and Cyclophilin A. By sterically hindering RAS effector protein binding and covalently bonding with Cys-13, it creates an irreversible inhibitory complex that prevents the proliferation of KRASG13C mutant cancer cells. RM-041 can induce tumor regression in KRASG13C cell and xenograft models and shows synergistic effects when combined with upstream node inhibitors (such as SHP2 inhibitors). It is applicable for research in non-small cell lung cancer.

KRAS G13C exhibits a higher intrinsic nucleotide exchange rate compared to KRAS G12C, reducing its reliance on reloading by GEF (guanine nucleotide exchange factors) and its sensitivity to upstream inhibitors such as SHP2 and SOS1. Therefore, therapies targeting tumors with the KRAS G13C mutation should directly inhibit KRAS G13C. Additionally, KRAS G13C shows unique sensitivity to specific GAPs (GTPase-activating proteins), including NF1. A preclinical combination therapy strategy could involve using RM-041 to specifically inhibit the mutant form of KRAS G13C, while also targeting upstream key nodes such as SHP2 to weaken the synergistic effects of wild-type RAS signaling.