RAF265

RAF265 (CHIR-265) is a novel, orally bioavailable dual inhibitor of RAF kinase and VEGFR2. RAF265 significantly enhanced TRAIL sensitivity in NCI-H727 and CM insulinoma cells by blocking Raf-MEK-Erk signalling. RAF265 strongly decreased Bcl-2 levels in those cell lines susceptible to its TRAIL-sensitizing action. RAF265 impaired in vitro differentiation of PBMCs to OCs induced by receptor activator of NF-kB ligand (RANKL) and M-CSF (IC(50) ≈ 160 nM). In parallel, RAF265 exerted a potent inhibition of OC resorptive capacity (IC(50) ≈ 20 nM). Moreover, RAF265 exhibits reduced pMEK1, reduced proliferation based upon reduced Ki-67, cyclin D1 and polo-like kinase1 levels, and induction of the apoptosis mediator BCL2-like 11. Using Raf-MEK-Erk pathway inhibitors and TRAIL together might offer a novel therapeutic strategy in NET disease.