State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University , Chengdu, 610041, China.
Sichuan Industrial Institute of Antibiotics, Chengdu University , Chengdu 610052, China.
J Med Chem. 2017 May 11;60(9):4023-4035. doi: 10.1021/acs.jmedchem.7b00357. Epub 2017 Apr 24.
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.
PI3K/AKT/mTOR 通路的功能失调信号在癌症中及其在细胞生长和存活中的关键作用使其成为癌症治疗的理想靶点。我们已经制备了一系列二吗啉取代的噻吩并嘧啶衍生物，并在体外和体内进行了评估。其中，化合物 14o 被鉴定为一种双重 Class I PI3K 和 mTOR 激酶抑制剂，与 Class I PI3K 抑制剂 1（pictilisib，GDC-0941）相比，对 mTOR 的抑制作用提高了约 8 倍。Western blot 分析证实，化合物 14o 通过抑制人癌细胞系中 AKT 和 S6 的磷酸化来调节细胞 PI3K/AKT/mTOR 通路的机制。此外，化合物 14o 在 SKOV-3 和 U87MG 肿瘤异种移植模型中表现出显著的疗效，而不会导致明显的体重减轻和毒性。
