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.

中文翻译：

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咪唑并[1,2-b]哒嗪衍生物作为mTOR抑制剂的设计，合成及生物学评价。

ATP竞争性mTOR抑制剂已被研究为潜在的抗肿瘤药物。基于已知的mTOR抑制剂的构效关系，合成并表征了一系列新型咪唑并[1,2-b]哒嗪衍生物。通过SRB分析评估了这些化合物对六种人类癌细胞系的抗增殖活性。咪唑并[1,2-b]哒嗪二芳基脲衍生物A15-A24表现出显着的抗增殖活性，尤其是针对非小细胞肺癌A549和H460，IC50值为0.02μM至20.7μM。其中，化合物A17和A18表现出mTOR抑制活性，IC50分别为0.067μM和0.062μM。对化合物A17和A18的更详细分析表明，它们在细胞水平上诱导G1期细胞周期停滞并抑制AKT和S6的磷酸化。此外，在已建立的裸鼠A549异种移植模型中观察到了A17在体内的明显抗癌作用。