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

被引:67
作者
Yu, Ya'nan [1 ]
Han, Yuqiao [1 ]
Zhang, Fupo [1 ]
Gao, Zhenmei [1 ]
Zhu, Tong [1 ]
Dong, Suzhen [1 ]
Ma, Mingliang [1 ,2 ]
机构
[1] East China Normal Univ, Shanghai Engn Res Ctr Mol Therapeut & New Drug De, Sch Chem & Mol Engn, Shanghai 200062, Peoples R China
[2] East China Normal Univ, Key Lab Brain Funct Genom, Minist Educ, Shanghai 200062, Peoples R China
基金
中国国家自然科学基金;
关键词
PHASE-I; PI3K; MTOR; PATHWAY; P110-ALPHA; CANCER;
D O I
10.1021/acs.jmedchem.9b01736
中图分类号
R914 [药物化学];
学科分类号
100701 ;
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.
引用
收藏
页码:3028 / 3046
页数:19
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