Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, 610041, PR China; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan, 610041, PR China.
Department of Pharmacy, Qionglai Medical Center Hospital of Sichuan Province, Chengdu, Sichuan, 611530, PR China.
Eur J Med Chem. 2020 Mar 1;189:112076. doi: 10.1016/j.ejmech.2020.112076. Epub 2020 Jan 23.
In this study, a series of thieno [2,3-d]pyrimidine derivatives were designed, synthesized and evaluated as novel AKT1 inhibitors. In vitro antitumor assay results showed that compounds 9d-g and 9i potently suppressed the enzymatic activities of AKT1 and potently inhibited the proliferation of HepG2, Hep3B, Huh-7 and SMMC-7721 cancer cell lines. Among these derivatives, the compound 9f demonstrated the best inhibitory activities on AKT1 (IC50 = 0.034 μM) and Huh-7 cell (IC50 = 0.076 μM). A panel of biological assays showed that compound 9f suppressed the cellular proliferation of Huh-7 through Akt/mTOR signaling pathway mediated autophagy mechanism. Furthermore, the antitumor capacity of 9f was validated in the subcutaneous Huh-7 xenograft models. Together, our results demonstrate that a novel small-molecule Akt1 inhibitor induces autophagy associated death in hepatocellular carcinoma, which may afford a potential drug candidate for targeted cancer therapy.
在这项研究中，设计、合成并评价了一系列噻吩并[2,3-d]嘧啶衍生物，作为新型 AKT1 抑制剂。体外抗肿瘤试验结果表明，化合物 9d-g 和 9i 能有效抑制 AKT1 的酶活性，并能有效抑制 HepG2、Hep3B、Huh-7 和 SMMC-7721 癌细胞系的增殖。在这些衍生物中，化合物 9f 对 AKT1（IC50=0.034μM）和 Huh-7 细胞（IC50=0.076μM）表现出最好的抑制活性。一系列生物学试验表明，化合物 9f 通过 Akt/mTOR 信号通路介导的自噬机制抑制 Huh-7 细胞的增殖。此外，9f 的抗肿瘤能力在皮下 Huh-7 异种移植模型中得到了验证。总之，我们的研究结果表明，新型小分子 Akt1 抑制剂通过诱导自噬相关死亡来抑制肝癌，这可能为肝癌的靶向治疗提供一种有潜力的候选药物。
