RMC5127 is an oral and mutation-selective inhibitor of RASG12V (ON) that inhibits the GTP-bound (ON) form of RAS G12V through the formation of a high-affinity triplex with central nervous system (CNS) permeability and brain permeability. RMC5127 inhibits RAS pathway activity in vitro in KRAS G12V mutant human cancer cells and cellular proliferation, and antitumor activity in preclinical intracranial xenograft models and subcutaneous CDX and PDX models of KRAS G12V mutant NSCLC, PDAC and CRC.

RMC5127 drove deep suppression of RAS pathway activity, inhibited cell proliferation, and induced apoptosis in a panel of KRASG12V mutant human cancer cells in vitro but only caused submaximal inhibition in the panel of K/N/HRAS wildtype cancer cells, indicative of selectivity for KRASG12V over K/N/HRAS wildtype[1].

RMC5127 showed profound and durable anti-tumor activity in vivo in multiple KRASG12V-mutant cancer models, including subcutaneous CDX and PDX models of NSCLC, pancreatic cancer (PDAC), and colorectal cancer (CRC).RMC5127 also demonstrated brain penetration, with dose-dependent exposure in whole brain tissue of naïve mice. In an intracranial xenograft model of KRASG12V-mutant tumors, RMC5127 achieved comparable brain tumor drug exposure, induced strong pharmacodynamic effects, and drove significant tumor regression at well-tolerated doses[1].