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

  • J Med Chem. 2020 Mar 26;63(6):3028-3046. doi: 10.1021/acs.jmedchem.9b01736.
Ya'nan Yu  1 ,  Yuqiao Han  1 ,  Fupo Zhang  1 ,  Zhenmei Gao  1 ,  Tong Zhu  1 ,  Suzhen Dong  1 ,  Mingliang Ma  1  2
Affiliations
  • 1. 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.
  • 2. Key Laboratory of Brain Functional Genomics, Ministry of Education, East China Normal University, Shanghai 200062, P. R. China.
PMID: 32069401 DOI: 10.1021/acs.jmedchem.9b01736
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-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.