To identify compounds with potent anti-tumor efficacy against various human cancers, we designed and synthesized dual inhibitors of c-Met and VEGFR2 kinases. The design of dual c-Met and VEGFR2 inhibitors were based on our VEGFR2 inhibitor which contains imidazo[1,2-b]pyridazine scaffold as a hinge binder. After lead optimization of this scaffold to enhance c-Met and VEGFR2 activities, one compound of particular note was the imidazo[1,2-a]pyridine derivative A  bearing a 2-pyridone ring, which strongly inhibited enzyme activities of both c-Met and VEGFR2 (IC50 = 1.9, 2.2 nM). It potently suppressed proliferation of c-Met-addicted MKN45 cells and VEGF-stimulated human umbilical vein endothelial cells (GI50 = 5.0, 1.8 nM). Compound A  exhibited dose-dependent anti-tumor efficacy in a MKN45 mouse xenograft model (T/C = 4% at a dose of 5 mg/kg qd). In this poster, details of the design, synthesis, and biological evaluation of the imidazo[1,2-b]pyridazine and imidazo[1,2-a]pyridine derivatives will be presented.

Structure-based design, synthesis, and evaluation of imidazo[1,2-<i>b</i>]pyridazine and imidazo[1,2-<i>a</i>]pyridine derivatives as dual inhibitors of c-Met and VEGFR2 kinases

246th National Meeting (2013)

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Structure-based design, synthesis, and evaluation of imidazo[1,2-b]pyridazine and imidazo[1,2-a]pyridine derivatives as dual inhibitors of c-Met and VEGFR2 kinases