RMC-6236

RMC-6236 is an orally active, potent RAS inhibitor that targets the active, GTP-bound wild-type (RAS-RAF complex disruption IC50 = 66/82/85 nM using NRAS/HRAS/KRAS) and mutant variants (IC50 = 28-200 nM) of canonical RAS isoforms. RMC-6236 inhibits RAS-mediated cellular signaling (pERK IC50 = 0.25-4.5 nM in 12 cancer cultures) and RAS-dependent cancer proliferation both in cultures (IC50 = 1.2 nM/HPAC and 1.4 nM/Capan-2) and in KRASG12X xenograft models in mice in vivo (10-25 mg/kg/day p.o.), including NCI-H441 (KRASG12V/WT, NSCLC), NCI-H358 (KRASG12C/WT, NSCLC) , Capan-2 (KRASG12V/WT, PDAC) and HPAC (KRASG12D/WT, PDAC).