RMC-4998 is an orally active inhibitor targeting the active or GTP-bound state of the KRASG12C mutant. RMC-4998 can form a ternary complex with intracellular CYPA and the activated KRASG12C mutant, with an IC50 value of 28 nM. RMC-4998 can inhibit ERK signaling in KRASG12C mutant cancer cells and induce apoptosis. RMC-4998 can be used for tumor research.
RMC-4998 (100 nM, 120 h) disrupts oncogenic signaling in KRASG12C mutant cells by recruiting cyclophilin A (CYPA) to the active state of mutant KRAS[1].RMC-4998 can inhibit the expression of ERK signaling related proteins and cell proliferation in KRASG12C mutant cancer cells[1].RMC-4998 (0-1000 nM, 72 h) inhibits lung cancer cell viability by suppressing the PI3K/mTOR and ERK signaling pathways[2].RMC-4998 (30 nM, 96 h) can inhibit ERK protein phosphorylation and suppress LU65 cell viability[3].
RMC-4998 (10-200 mg/kg; once daily; 28 days; p.o.) inhibits ERK phosphorylation in tumors and exhibits anti-tumor activity in mice carrying NCI-H358 xenografts[1].RMC-4998 (80 mg/kg; once daily; 4 weeks; p.o.) can promote tumor regression in non-small cell lung cancer mice and has anti-tumor activity[2].RMC-4998 (100 mg/kg; once daily; p.o.) induces tumor regression and inhibits ERK phosphorylation expression in sotorasib-R LU65 xenograft mice[3].
References:
[1]. Schulze CJ, et al. Chemical remodeling of a cellular chaperone to target the active state of mutant KRAS. Science. 2023 Aug 18;381(6659):794-799.
[2]. Kitai H,et al. Combined inhibition of KRASG12C and mTORC1 kinase is synergistic in non-small cell lung cancer. Nat Commun. 2024 Jul 19;15(1):6076.
[3]. Solanki H S, et al. RTK signaling and WT RAS activity as vulnerabilities in tumors with acquired resistance to GDP-state selective KRASG12C inhibitors in preclinical models[J]. Cancer Research, 2024, 84(6_Supplement): 1924-1924.