PLX647 is a dual inhibitor of the receptor tyrosine kinases FMS and KIT (IC50s = 28 and 16 nM, respectively). It is selective for FMS and KIT but does inhibit FLT3 and KDR (IC50s = 91 and 130 nM, respectively) in a panel of 400 kinases at a concentration of 1 μM. PLX647 inhibits proliferation of Ba/F3 cells expressing constitutively active FMS or KIT (IC50s = 92 and 180 nM, respectively) as well as ligand-dependent growth of M-NFS-60 and M-07e cells that express endogenous FMS and KIT, respectively (IC50s = 380 and 230 nM, respectively). It has no effect on HEK293T or HepG2 cells that lack FMS and KIT (IC50 = >50 μM) or Ba/F3 cells overexpressing KDR (IC50 = >5 μM). PLX647 also inhibits differentiation of human osteoclast precursor cells (IC50 = 170 nM). In vivo, PLX647 (40 mg/kg) reduces TNF-α and IL-6 release in a rat model of LPS-induced cytokine release. It reduces mast cell degranulation in a mouse model of passive cutaneous anaphylaxis (PCA) and inhibits bone destruction and delays disease progression in a mouse model of collagen-induced arthritis (CIA). PLX647 also reverses bone osteolysis and allodynia in a syngeneic rat model of cancer-induced bone pain.
