Discovery of Akt Kinase Inhibitors through Structure-Based Virtual Screening and Their Evaluation as Potential Anticancer Agents

International Journal of Molecular Sciences

Chih-Hung Chuang⁴  Ta-Chun Cheng³  Yu-Ling Leu¹  Kuo-Hsiang Chuang³  Shey-Cherng Tzou⁵  Chien-Shu Chen² 

[1] Department of Pharmacy, Chia Nan University of Pharmacy and Science, Tainan 71710, Taiwan; E-Mail:;School of Pharmacy, China Medical University, Taichung 40402, Taiwan;Graduate Institute of Pharmacognosy, Taipei Medical University, Taipei 11031, Taiwan; E-Mails:;Institutes of Basic Medical Sciences, National Cheng Kung University, Tainan 70101, Taiwan; E-Mail:;Department of Biological Science and Technology, National Chiao Tung University, Hsinchu 30050, Taiwan; E-Mail:

关键词: Akt kinase;    inhibitors;    cancer;    virtual screening;    docking;   

DOI  :  10.3390/ijms16023202

来源: mdpi

【 摘 要 】

Akt acts as a pivotal regulator in the PI3K/Akt signaling pathway and represents a potential drug target for cancer therapy. To search for new inhibitors of Akt kinase, we performed a structure-based virtual screening using the DOCK 4.0 program and the X-ray crystal structure of human Akt kinase. From the virtual screening, 48 compounds were selected and subjected to the Akt kinase inhibition assay. Twenty-six of the test compounds showed more potent inhibitory effects on Akt kinase than the reference compound, H-89. These 26 compounds were further evaluated for their cytotoxicity against HCT-116 human colon cancer cells and HEK-293 normal human embryonic kidney cells. Twelve compounds were found to display more potent or comparable cytotoxic activity compared to compound H-89 against HCT-116 colon cancer cells. The best results were obtained with Compounds a46 and a48 having IC₅₀ values (for HCT-116) of 11.1 and 9.5 µM, respectively, and selectivity indices (IC₅₀ for HEK-293/IC₅₀ for HCT-116) of 12.5 and 16.1, respectively. Through structure-based virtual screening and biological evaluations, we have successfully identified several new Akt inhibitors that displayed cytotoxic activity against HCT-116 human colon cancer cells. Especially, Compounds a46 and a48 may serve as useful lead compounds for further development of new anticancer agents.

【 授权许可】

CC BY   
© 2015 by the authors; licensee MDPI, Basel, Switzerland.