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Int. J. Mol. Sci. 2015, 16(2), 3202-3212;

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

Institutes of Basic Medical Sciences, National Cheng Kung University, Tainan 70101, Taiwan
Graduate Institute of Pharmacognosy, Taipei Medical University, Taipei 11031, Taiwan
Department of Pharmacy, Chia Nan University of Pharmacy and Science, Tainan 71710, Taiwan
Department of Biological Science and Technology, National Chiao Tung University, Hsinchu 30050, Taiwan
School of Pharmacy, China Medical University, Taichung 40402, Taiwan
These authors contributed equally to this work.
Author to whom correspondence should be addressed.
Academic Editor: Chang Won Choi
Received: 21 December 2014 / Revised: 15 January 2015 / Accepted: 27 January 2015 / Published: 2 February 2015
(This article belongs to the Section Biochemistry)
Full-Text   |   PDF [2986 KB, uploaded 2 February 2015]   |  


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. View Full-Text
Keywords: Akt kinase; inhibitors; cancer; virtual screening; docking Akt kinase; inhibitors; cancer; virtual screening; docking

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Chuang, C.-H.; Cheng, T.-C.; Leu, Y.-L.; Chuang, K.-H.; Tzou, S.-C.; Chen, C.-S. Discovery of Akt Kinase Inhibitors through Structure-Based Virtual Screening and Their Evaluation as Potential Anticancer Agents. Int. J. Mol. Sci. 2015, 16, 3202-3212.

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