Revolution Medicines Announces Publication Describing Molecular Basis of Tri-Complex Inhibitors Targeting Oncogenic RAS(ON) Proteins
19 Aug 2023
AACR
Science Report on KRASG12C(ON)-Selective Inhibitors Provides Preclinical Proof-of-Principle for Company's RAS Innovation Engine and Broad Pipeline
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 KRASG12C 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. KRASG12C(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 KRASG12C-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.”
The investigational agent RMC-6291, an oral, selective, covalent inhibitor of KRASG12C(ON) designed to treat patients with cancers driven by the KRASG12C variant, is the first of the company’s mutant-selective RAS(ON) inhibitors to enter clinical development and the first reported clinical-stage inhibitor of KRASG12C that uses this highly differentiated mechanism of action. Revolution Medicines is currently evaluating RMC-6291 as monotherapy in a Phase 1/1b trial in patients with advanced KRASG12C mutant solid tumors (NCT05462717).
The manuscript published In Science is entitled, “Chemical remodeling of a cellular chaperone to target the active state of mutant KRAS” and can be accessed at https://www.science.org/doi/10.1126/science.adg9652.
About Revolution Medicines, Inc.
Revolution Medicines is a clinical-stage oncology company developing novel targeted therapies for RAS-addicted cancers. The company’s R&D pipeline comprises RAS(ON) Inhibitors designed to suppress diverse oncogenic variants of RAS proteins, and RAS Companion Inhibitors for use in combination treatment strategies. The company’s RAS(ON) Inhibitors RMC-6236 (RASMULTI), RMC-6291(KRASG12C) and RMC-9805 (KRASG12D) are currently in clinical development. Additional RAS(ON) Inhibitors in the company’s pipeline include RMC-0708 (KRASQ61H) which is currently in IND-enabling development, RMC-8839 (KRASG13C), and additional compounds targeting other RAS variants. RAS Companion Inhibitors in clinical development include RMC-4630 (SHP2) and RMC-5552 (mTORC1/4EBP1).
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