RMC-7977

RMC-7977 is an orally active triple-complex RAS inhibitor that can simultaneously bind to cyclophilin A (CYPA) (Kd = 195 nM) and KRAS (G12V) (Kd = 292 μM). It exhibits broad-spectrum inhibitory activity against KRAS, NRAS, and HRAS proteins and their various wild-type and mutant variants. RMC-7977 induces apoptosis by inhibiting the phosphorylation of ERK, CRAF, and RSK, as well as increasing PARP cleavage. This leads to tumor regression, reduces resistance in KRASG12C cancer models, and demonstrates good tolerability across various RAS cancer models[1][2][3].

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[1]Singh M, et al. Concurrent inhibition of oncogenic and wild-type RAS-GTP for cancer therapy. Research Square; 2023.|[2]Popescu B, et al. RAS MULTI (ON) inhibitor RMC-7977 targets oncogenic RAS mutations and overcomes RAS/MAPK-mediated resistance to FLT3 inhibitors in AML models[J]. Blood, 2023, 142: 2793.|[3]Wasko UN, et al. Tumour-selective activity of RAS-GTP inhibition in pancreatic cancer. Nature. 2024 May;629(8013):927-936.