Design, Synthesis, and Biological Evaluation of Dimorpholine Substituted Thienopyrimidines as Potential Class I PI3K/mTOR Dual Inhibitors

  • J Med Chem. 2017 May 11;60(9):4023-4035. doi: 10.1021/acs.jmedchem.7b00357.
Miao Zhan  1 ,  Yufang Deng  1 ,  Lifeng Zhao  2 ,  Guoyi Yan  1 ,  Fangying Wang  1 ,  Ye Tian  1 ,  Lanxi Zhang  1 ,  Hongxia Jiang  1 ,  Yuanwei Chen  1  3
Affiliations
  • 1. State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University , Chengdu, 610041, China.
  • 2. Sichuan Industrial Institute of Antibiotics, Chengdu University , Chengdu 610052, China.
  • 3. Hinova Pharmaceuticals Inc. , Suite 402, Building B, #5 South KeYuan Road, Chengdu, 610041, China.
PMID: 28409639 DOI: 10.1021/acs.jmedchem.7b00357
Abstract

Dysfunctional signaling of the PI3K/Akt/mTOR pathway in Cancer and its crucial role in cell growth and survival have made it a much desired target for Cancer therapeutics. A series of dimorpholine substituted thienopyrimidine derivatives had been prepared and evaluated in vitro and in vivo. Among them, compound 14o was identified as a dual Class I PI3K and mTOR kinase inhibitor, which had an approximately 8-fold improvement in mTOR inhibition relative to the class I PI3K Inhibitor 1 (pictilisib, GDC-0941). Western blot analysis confirmed the 14o mechanistic modulation of the cellular PI3K/Akt/mTOR pathway through inhibiting phosphorylation of both Akt and S6 in human Cancer cell lines. In addition, 14o demonstrated significant efficacy in SKOV-3 and U87MG tumor xenograft models without causing significant weight loss and toxicity.

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