RAF709 is a potent inhibitor of B-RAF and C-RAF (IC50s = 0.4 and 0.5 nM, respectively). It is selective for RAF kinases exhibiting >99% inhibition of only B-RAF, B-RAFV600E, and C-RAF in a panel of 456 kinases. However, DDR1, DDR2, FRK, and PDGFRβ are also inhibited by >80% at a concentration of 1 μM. RAF709 inhibits phosphorylation of MEK and ERK (EC50s = 0.02 and 0.1 μM, respectively) with minimal paradoxical activation, stabilizes BRAF-CRAF dimers (EC50 = 0.8 μM), and reduces proliferation of Calu-6 RAS mutant cells (EC50 = 0.95 μM). In a Calu-6 mouse non-small cell lung cancer (NSCLC) xenograft model, RAF709 (10-200 mg/kg) reduces ERK phosphorylation and decreases tumor volume in a dose-dependent manner without affecting total body weight.
