设计、合成并评价咪唑并[1,2-a]吡啶衍生物作为新型的 PI3K/mTOR 双重抑制剂。
Design, Synthesis, and Biological Evaluation of Imidazo[1,2-]pyridine Derivatives as Novel PI3K/mTOR Dual Inhibitors.
机构信息
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, P. R. China.
Key Laboratory of Brain Functional Genomics, Ministry of Education, East China Normal University, Shanghai 200062, P. R. China.
出版信息
J Med Chem. 2020 Mar 26;63(6):3028-3046. doi: 10.1021/acs.jmedchem.9b01736. Epub 2020 Feb 27.
PI3K-Akt-mTOR signaling pathway has been validated as an effective targeting pathway for cancer therapy. However, no PI3K/mTOR dual inhibitor has been approved by the FDA yet. Therefore, it is still essential to discover a candidate with good efficacy and low toxicity. In our design, a series of imidazo[1,2-]pyridine derivatives had been synthesized and subjected to activity assessment and . was proved to be a potent PI3K/mTOR dual inhibitor with excellent kinase selectivity, modest plasma clearance, and acceptable oral bioavailability. Besides, displayed significant inhibition of tumor growth in HCT116 and HT-29 xenografts without obvious effect on body weight.
PI3K-Akt-mTOR 信号通路已被证实为癌症治疗的有效靶点。然而，目前还没有 FDA 批准的 PI3K/mTOR 双重抑制剂。因此，发现具有良好疗效和低毒性的候选药物仍然至关重要。在我们的设计中，已经合成了一系列咪唑并[1,2-a]吡啶衍生物，并对其进行了活性评估。结果表明，化合物 是一种有效的 PI3K/mTOR 双重抑制剂，具有优异的激酶选择性、适度的血浆清除率和可接受的口服生物利用度。此外，化合物 在 HCT116 和 HT-29 异种移植瘤模型中表现出显著的肿瘤生长抑制作用，且对体重无明显影响。
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