gdc-0068 and Carcinoma--Hepatocellular

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.

Topics: Animals; Antineoplastic Agents; Autophagic Cell Death; Carcinoma, Hepatocellular; Cell Proliferation; Drug Discovery; Humans; Liver Neoplasms; Mice; Mice, Nude; Piperazines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Signal Transduction; Tumor Cells, Cultured; Xenograft Model Antitumor Assays