Structure-based design, synthesis, and evaluation of imidazo[1,2-b]pyridazine and imidazo[1,2-a]pyridine derivatives as novel dual c-Met and VEGFR2 kinase inhibitors.
To identify compounds with potent antitumor efficacy for various human cancers, we aimed to synthesize compounds that could inhibit c-mesenchymal epithelial transition factor (c-Met) and vascular endothelial growth factor receptor 2 (VEGFR2) kinases. We designed para-substituted inhibitors by using co-crystal structural information from c-Met and VEGFR2 in complex with known inhibitors. This led to the identification of compounds 3a and 3b, which were capable of suppressing both c-Met and VEGFR2 kinase activities. Further optimization resulted in pyrazolone and pyridone derivatives, which could form intramolecular hydrogen bonds to enforce a rigid conformation, thereby producing potent inhibition. One compound of particular note was the imidazo[1,2-a]pyridine derivative (26) bearing a 6-methylpyridone ring, which strongly inhibited both c-Met and VEGFR2 enzyme activities (IC50=1.9, 2.2 nM), as well as proliferation of c-Met-addicted MKN45 cells and VEGF-stimulated human umbilical vein endothelial cells (IC50=5.0, 1.8 nM). Compound 26 exhibited dose-dependent antitumor efficacy in vivo in MKN45 (treated/control ratio [T/C]=4%, po, 5mg/kg, once-daily) and COLO205 (T/C=13%, po, 15 mg/kg, once-daily) mouse xenograft models.
['Matsumoto|Shigemitsu|S|', 'Miyamoto|Naoki|N|', 'Hirayama|Takaharu|T|', 'Oki|Hideyuki|H|', 'Okada|Kengo|K|', 'Tawada|Michiko|M|', 'Iwata|Hidehisa|H|', 'Nakamura|Kazuhide|K|', 'Yamasaki|Seiji|S|', 'Miki|Hiroshi|H|', 'Hori|Akira|A|', 'Imamura|Shinichi|S|']
D000818:Animals D000970:Antineoplastic Agents D002460:Cell Line D049109:Cell Proliferation D004305:Dose-Response Relationship, Drug D015195:Drug Design D004354:Drug Screening Assays, Antitumor D005260:Female D006574:Heterocyclic Compounds, 2-Ring D006801:Humans D051379:Mice D008807:Mice, Inbred BALB C D008862:Microsomes, Liver D008958:Models, Molecular D015394:Molecular Structure D009536:Niacinamide D047428:Protein Kinase Inhibitors D019859:Proto-Oncogene Proteins c-met D011725:Pyridines D012995:Solubility D013329:Structure-Activity Relationship D040301:Vascular Endothelial Growth Factor Receptor-2
Imidazo[1,2-b]pyridazine Imidazo[1,2-a]pyridine c-Met VEGFR2 Pyridone WXOGYBWIHWKUMA-UHFFFAOYSA-N