LY2801653

LY2801653 demonstrated in vitro effects on MET pathway-dependent cell scattering and cell proliferation; in vivo anti-tumor effects in MET amplified (MKN45), MET autocrine (U-87MG, and KP4) and MET over-expressed (H441) xenograft models; and in vivo vessel normalization effects. LY2801653 also maintained potency against 13 MET variants, each bearing a single-point mutation. In subsequent nonclinical characterization, LY2801653 was found to have potent activity against several other receptor tyrosine oncokinases including MST1R, FLT3, AXL, MERTK, TEK, ROS1, DDR1/2 and against the serine/threonine kinases MKNK1/2. LY2801653 was more efficacious than the MET/ALK/RON/ROS inhibitor crizotinib with a distinct pattern of downstream signaling effects. In classic and orthotopic mouse xenograft models of lung cancer, LY2801653 decreased tumor growth, dramatically inhibiting mitotic events and angiogenesis.