☆ 4.7 Article

Design, Synthesis, and Biological Evaluation of Imidazo[1,2-a]pyridine Derivatives as Novel PI3K/mTOR Dual Inhibitors

JOURNAL OF MEDICINAL CHEMISTRY (2020)

期刊

JOURNAL OF MEDICINAL CHEMISTRY

卷 63, 期 6, 页码 3028-3046

出版社

AMER CHEMICAL SOC

DOI: 10.1021/acs.jmedchem.9b01736

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Chemistry, Medicinal

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National Natural Science Foundation of China [21572067]

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Reagent

摘要

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-a]pyridine derivatives had been synthesized and subjected to activity assessment in vitro and in vivo. 15a was proved to be a potent PI3K/mTOR dual inhibitor with excellent kinase selectivity, modest plasma clearance, and acceptable oral bioavailability. Besides, 15a displayed significant inhibition of tumor growth in HCT116 and HT-29 xenografts without obvious effect on body weight.

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