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.

中文翻译：

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新型akt1抑制剂的发现可诱导肝癌细胞自噬相关的死亡。

在这项研究中，设计，合成和评估了一系列噻吩并[2,3-d]嘧啶衍生物，并将其作为新型AKT1抑制剂进行了评估。体外抗肿瘤测定结果表明，化合物9d-g和9i有效抑制AKT1的酶活性，并有效抑制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）表现出最佳的抑制活性。一组生物学实验表明，化合物9f通过Akt / mTOR信号通路介导的自噬机制抑制了Huh-7的细胞增殖。此外，在皮下Huh-7异种移植模型中验证了9f的抗肿瘤能力。一起，