2. Academic Validation
  3. Discovery of novel akt1 inhibitor induces autophagy associated death in hepatocellular carcinoma cells

Discovery of novel akt1 inhibitor induces autophagy associated death in hepatocellular carcinoma cells

  • Eur J Med Chem. 2020 Mar 1:189:112076. doi: 10.1016/j.ejmech.2020.112076.
Meng Yu 1,  Minghui Zeng 2,  Zhaoping Pan 3,  Fengbo Wu 3,  Li Guo 4,  Gu He 5
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Pharmacy, Qionglai Medical Center Hospital of Sichuan Province, Chengdu, Sichuan, 611530, PR China.
  • 3 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan, 610041, PR China.
  • 4 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.
  • 5 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan, 610041, PR China. Electronic address: hegu@scu.edu.cn.
PMID: 32007668 DOI: 10.1016/j.ejmech.2020.112076
Abstract

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.

Keywords

Akt1; Autophagy; Hepatocellular carcinoma; Inhibitor.

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