2. Academic Validation
  3. Design, synthesis, and biological evaluation of imidazo[1,2-b]pyridazine derivatives as mTOR inhibitors

Design, synthesis, and biological evaluation of imidazo[1,2-b]pyridazine derivatives as mTOR inhibitors

  • Eur J Med Chem. 2017 Mar 31:129:135-150. doi: 10.1016/j.ejmech.2017.02.015.
Beibei Mao 1,  Shanyun Gao 1,  Yiran Weng 1,  Liangren Zhang 2,  Lihe Zhang 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China.
  • 2 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China. Electronic address: liangren@bjmu.edu.cn.
PMID: 28235701 DOI: 10.1016/j.ejmech.2017.02.015
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 IC50 values ranging from 0.02 μM to 20.7 μM. Among them, compounds A17 and A18 showed mTOR inhibitory activity with IC50 of 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.

Keywords

Anti-proliferative activity; Anticancer; Imidazo[1,2-b]pyridazine; mTOR inhibitors.

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