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

doi:10.3390/ijms16023202

Chia Nan University of Pharmacy & Science Institutional Repository > 藥理學院 > 藥學系(所) > 期刊論文 > Item 310902800/29595

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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 inhibitors cancer virtual screening docking
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
顯示於類別:	[藥學系(所)] 期刊論文

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