Revolution Medicines Announces Publication Describing Molecular Basis of Tri-Complex Inhibitors Targeting Oncogenic RAS(ON) Proteins

Science Report on KRAS^G12C(ON)-Selective Inhibitors Provides Preclinical Proof-of-Principle for Company's RAS Innovation Engine and Broad Pipeline

REDWOOD CITY, Calif., Aug. 17, 2023 (GLOBE NEWSWIRE) -- Revolution Medicines, Inc. (Nasdaq: RVMD), a clinical-stage oncology company developing targeted therapies for RAS-addicted cancers, today announced the publication of a peer-reviewed research paper in Science. This original research was led by scientists at Revolution Medicines and conducted in collaboration with researchers from Memorial Sloan Kettering Cancer Center.

The paper describes the Revolution Medicines tri-complex inhibitor approach to developing novel small molecules with high affinity and selectivity for the active state of mutant RAS, or RAS(ON), proteins that are common causes of human cancer and were previously considered undruggable. Specifically, it describes the creation of innovative, natural product-inspired, orally bioavailable small molecules, including the tool compound RMC-4998 and the clinical candidate RMC-6291. These compounds are shown to remodel the surface of the cellular chaperone cyclophilin A (CYPA) to create a neomorphic interface with affinity for active KRAS and achieve high selectivity for mutant KRAS^G12C via covalent, irreversible binding to the cysteine residue in the active state of this variant RAS protein that often drives formation of lung and colorectal cancers. KRAS^G12C(ON) trapped in these tri-complexes is sterically blocked from interacting with downstream effectors that transmit cancer-causing signals. Both RMC-4998 and RMC-6291 inactivate oncogenic signaling in KRAS^G12C-dependent tumor cells and drive deep and durable tumor regressions in human xenograft models of these cancers.

“This research serves as preclinical validation of our tri-complex RAS(ON) inhibitor platform and confirms our ability to design potent, selective small molecules that target KRAS mutations in their active or ON state,” said Steve Kelsey, M.D., president, research and development at Revolution Medicines. “These data provide the rationale for the RMC-6291 clinical program, our first mutant-selective RAS(ON) inhibitor to enter clinical development, which is currently underway. We look forward to sharing a preliminary report of the clinical profile for RMC-6291 at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics (Triple Meeting) in October 2023.”