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

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 imi...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2020-03, Vol.63 (6), p.3028-3046
Main Authors: Yu, Ya’nan, Han, Yuqiao, Zhang, Fupo, Gao, Zhenmei, Zhu, Tong, Dong, Suzhen, Ma, Mingliang
Format: Article
Language:English
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.9b01736