RMC-7977
[CAS# 2765082-12-8]

Identification

• Classification: Biochemical >> Inhibitor >> G protein coupled receptor(GPCR & G Protein)
• Name: RMC-7977
• Synonyms: (1S,5R)-N-[(7S,13S)-20-[5-(4-cyclopropylpiperazin-1-yl)-2-[(1S)-1-methoxyethyl]pyridin-3-yl]-21-ethyl-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.12,5.19,13.022,26]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-oxabicyclo[3.1.0]hexane-6-carboxamide
• Molecular Formula: C₄₇H₆₀N₈O₆S
• Molecular Weight: 865.09
• CAS Registry Number: 2765082-12-8
• SMILES: CCN1C2=C3C=C(C=C2)C4=CSC(=N4)C[C@@H](C(=O)N5CCC[C@H](N5)C(=O)OCC(CC3=C1C6=C(N=CC(=C6)N7CCN(CC7)C8CC8)[C@H](C)OC)(C)C)NC(=O)C9[C@H]1[C@@H]9COC1

Safety Data

• Hazard Symbols: GHS07 Warning
• Risk Statements: H302-H315-H319
• Safety Statements: P501-P270-P264-P280-P302+P352-P337+P313-P305+P351+P338-P362+P364-P332+P313-P301+P312+P330

Discovery and Applications

RMC-7977 is a small-molecule therapeutic agent developed as a selective inhibitor of the active, GTP-bound forms of KRAS, HRAS, and NRAS proteins. These RAS proteins are critical components of intracellular signaling pathways that regulate cell proliferation, survival, and differentiation. Mutations in RAS genes, particularly KRAS, are implicated in approximately 20–30% of human cancers, including pancreatic ductal adenocarcinoma, non-small cell lung cancer, and colorectal cancer. Targeting the active state of RAS proteins presents a promising strategy for treating RAS-driven malignancies.

The development of RMC-7977 was based on the concept of tri-complex inhibition, wherein the compound forms a ternary complex with cyclophilin A (CYPA) and the active form of RAS. This binding mechanism sterically hinders the interaction between RAS and its downstream effectors, thereby disrupting RAS-mediated signaling pathways. RMC-7977 was identified through structure-guided drug design and optimization, building upon a previously identified CYPA inhibitor derived from the natural product sanglifehrin A.

In preclinical studies, RMC-7977 demonstrated potent inhibitory activity against both mutant and wild-type RAS proteins in their active GTP-bound state. The compound exhibited low nanomolar potency in cellular assays, with an effective concentration (EC50) for ERK phosphorylation inhibition of approximately 0.42 nM and for cell proliferation inhibition of approximately 2.2 nM. These findings suggest that RMC-7977 can effectively suppress RAS-driven signaling in cancer cells.

The therapeutic potential of RMC-7977 was further evaluated in various cancer models. In pancreatic ductal adenocarcinoma models, RMC-7977 treatment resulted in significant tumor regression and prolonged survival in mouse models. Importantly, the compound demonstrated a favorable safety profile, with minimal effects observed in normal tissues compared to tumor tissues. This selective activity is attributed to the compound's ability to preferentially target the active forms of RAS proteins present in cancer cells.

RMC-7977 also showed efficacy in overcoming resistance to KRAS(G12C) inhibitors. In models where resistance to KRAS(G12C) inhibitors had developed due to reactivation of RAS signaling, RMC-7977 effectively inhibited RAS pathway signaling and suppressed tumor growth. This suggests that RMC-7977 may serve as a valuable therapeutic option for patients whose tumors have acquired resistance to existing KRAS-targeted therapies.

The compound's broad-spectrum activity against multiple RAS isoforms and its ability to target both mutant and wild-type forms of RAS proteins in their active state position RMC-7977 as a promising candidate for the treatment of RAS-driven cancers. Ongoing clinical studies are expected to provide further insights into the efficacy and safety of RMC-7977 in human patients.

References

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