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

Abstract

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