title: Design, synthesis, and biological evaluation of imidazo[1,2-b]pyridazine derivatives as mTOR inhibitors.
abstract: ATP-competitive mTOR inhibitors have been studied as potential antitumor agents. Based on the structure-activity relationship of known mTOR inhibitors, a series of novel imidazo[1,2-b]pyridazine derivatives were synthesized and characterized. The anti-proliferative activities of these compounds were evaluated by SRB assay against six human cancer cell lines. Imidazo[1,2-b]pyridazine diaryl urea derivatives A15-A24 exhibited significant anti-proliferative activity especially against non-small cell lung cancer A549 and H460 with IC50values ranging from 0.02 μM to 20.7 μM. Among them, compounds A17 and A18 showed mTOR inhibitory activity with IC50of 0.067 μM and 0.062 μM, respectively. A more detailed analysis of compounds A17 and A18 showed that they induced G1-phase cell cycle arrest and suppressed the phosphorylation of AKT and S6 at cellular level. Moreover, obvious anticancer effect of A17 in vivo was observed in established nude mice A549 xenograft model.
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China.
authors.forename: Beibei
authors.initials: B
authors.lastname: Mao
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China.
authors.forename: Shanyun
authors.initials: S
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China.
authors.forename: Yiran
authors.initials: Y
authors.lastname: Weng
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China. Electronic address: liangren@bjmu.edu.cn.
authors.forename: Liangren
authors.initials: L
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China.
authors.forename: Lihe
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000072283:A549 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D064593:Heterografts; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D008819:Mice, Nude; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D011724:Pyridazines / Q000138:chemical synthesis / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: Anti-proliferative activity; Anticancer; Imidazo[1,2-b]pyridazine; mTOR inhibitors