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

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.

肿瘤中PI3K/AKT/mTOR通路的信号传导异常，且该通路在细胞生长与存活中发挥关键作用，使其成为癌症治疗领域极具吸引力的靶点。本研究合成了一系列二吗啉取代的噻吩并嘧啶衍生物，并开展了体内外活性评价。其中，化合物14o被鉴定为双靶点I类PI3K与mTOR激酶抑制剂，相较于I类PI3K抑制剂1（pictilisib，GDC-0941），其对mTOR的抑制活性提升约8倍。蛋白质免疫印迹（Western Blot）实验证实，化合物14o可通过抑制人癌细胞系中AKT与S6的磷酸化，对细胞PI3K/AKT/mTOR通路发挥机制性调控作用。此外，化合物14o在SKOV-3与U87MG肿瘤异种移植模型中展现出显著的抗肿瘤活性，且未引发明显的体重下降与毒性反应。