RMC-7977

RMC-7977 is an inhibitor of wild-type and mutant Ras protein-protein interactions.¹ It inhibits the interaction between wild-type K-Ras and seven activating mutation-containing K-Ras variants and C-RAF (EC₅₀s = 5.06-34.5 nM) and the same K-Ras variants and cyclophilin A (EC₅₀s = 1.27-9.12 nM) in bioluminescence resonance energy transfer (BRET) assays using U2OS cells expressing the human proteins. RMC-7977 also inhibits the protein-protein interactions between wild-type N-Ras, N-Ras^Q61K, N-Ras^Q61L, and N-Ras^Q61R and B-RAF (EC₅₀s = 57.7, 53.9, 145, and 181 nM, respectively, in time-resolved FRET (TR-FRET) assays) and wild-type H-Ras and H-Ras^G13R and B-RAF (EC₅₀s = 59.9 and 23.7 nM, respectively, in TR-FRET assays). It has antiproliferative activity against a panel of 183 K-Ras-dependent cancer cell lines (median EC₅₀ = 2.4 nM). RMC-7977 (10 nM) also reduces the proliferation of adagrasib-resistant NCI H358 non-small cell lung cancer (NSCLC) cells. It reduces tumor volumes in SW620 colon, HPAC pancreatic, and NCI H441 lung cancer mouse xenograft models when administered at a dose of 10 mg/kg per day.

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1. Holderfield, M., Lee, B.J., Jiang, J., et al. Concurrent inhibition of oncogenic and wild-type RAS-GTP for cancer therapy. Nature 629(8013), 919-926 (2024).