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    Please use this identifier to cite or link to this item: http://ir.cnu.edu.tw/handle/310902800/29595

    標題: Discovery of Akt Kinase Inhibitors through Structure-Based Virtual Screening and Their Evaluation as Potential Anticancer Agents
    作者: Chuang, Chih-Hung
    Cheng, Ta-Chun
    Leu, Yu-Ling
    Chuang, Kuo-Hsiang
    Tzou, Shey-Cherng
    Chen, Chien-Shu
    貢獻者: 藥學系
    關鍵字: Akt kinase
    virtual screening
    日期: 2015-02
    上傳時間: 2016-04-19 19:01:27 (UTC+8)
    出版者: Mdpi Ag
    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 mu M, 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.
    關聯: International Journal of Molecular Sciences, v.16 n.2, pp.3202-3212
    Appears in Collections:[藥學系(所)] 期刊論文

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