Revolution Medicines Announces Publications on the Discovery and Preclinical Profile of Representative of a New Class of RAS(ON) Multi-Selective Inhibitors Designed to Block Full Spectrum of Oncogenic RAS(ON) Proteins

Two original papers in Nature highlight the discovery and translational implications of RMC-7977, a RAS(ON) multi-selective tri-complex inhibitor that exhibits unprecedented anti-tumor activity in preclinical models of RAS-mutant pancreatic ductal adenocarcinoma (PDAC)

First paper demonstrates RMC-7977 successfully targets signaling by both mutant and wild-type forms of RAS to drive potent and durable inhibition of RAS-mutated cancers

Second paper highlights translation-focused research with RMC-7977, which drives deep and durable anti-tumor activity, at well-tolerated doses, across a wide range of RAS-mutated PDAC preclinical models

REDWOOD CITY, Calif., April 08, 2024 (GLOBE NEWSWIRE) -- Revolution Medicines, Inc. (Nasdaq: RVMD), a clinical-stage oncology company developing targeted therapies for patients with RAS-addicted cancers, today announced the publication of two peer-reviewed research papers in Nature. The first paper highlights the discovery and preclinical characterization of RMC-7977, a preclinical tool compound representative of a class of oral RAS(ON) multi-selective inhibitors, including the investigational drug candidate RMC-6236, that target multiple RAS variants. The second paper highlights the systematic evaluation of RMC-7977 in a wide range of preclinical models of PDAC. This original research was led by scientists at Revolution Medicines and conducted in collaboration with researchers from across the U.S. and Europe.

Oncogenic RAS proteins drive up to 30 percent of all human cancers, most notably non-small cell lung cancer (NSCLC), PDAC and colorectal cancer (CRC). RAS G12 mutations, such as G12D, G12V and G12C, predominate in human cancers. Approved KRAS-targeted cancer therapies target only one particular RAS mutation, KRAS G12C.

The first Nature paper describes RMC-7977, a RAS(ON) multi-selective inhibitor preclinical tool compound, which was designed to inhibit the full spectrum of oncogenic RAS mutations, including RAS codon 12 mutations (RAS G12X) as well as non-mutated wild-type RAS. RMC-7977 engages the intracellular chaperone cyclophilin A (CYPA) to form a binary complex that binds reversibly and with high affinity to RAS proteins that are in the active, GTP-bound or ON state. In preclinical studies, RMC-7977 demonstrated robust, durable anti-tumor activity at well-tolerated doses across a range of RAS-mutated NSCLC, PDAC and CRC models. Importantly, the preclinical study demonstrated that RAS(ON) multi-selective inhibitors, as represented by RMC-7977, have the potential to overcome some of the resistance mechanisms that have been shown to limit the clinical efficacy and durability of current KRAS(OFF) G12C-selective inhibitors, including adaptive signaling mechanisms mediated by activation of wild-type RAS.