title: Discovery of Akt kinase inhibitors through structure-based virtual screening and their evaluation as potential anticancer agents.
abstract: 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.
authors: Institutes of Basic Medical Sciences, National Cheng Kung University, Tainan 70101, Taiwan. a4132600@gmail.com.
authors: Chih-Hung
authors: CH
authors: Chuang
authors: Graduate Institute of Pharmacognosy, Taipei Medical University, Taipei 11031, Taiwan. chengtachun@gmail.com.
authors: Ta-Chun
authors: TC
authors: Cheng
authors: Department of Pharmacy, Chia Nan University of Pharmacy and Science, Tainan 71710, Taiwan. wyulinlu@gmail.com.
authors: Yu-Ling
authors: YL
authors: Leu
authors: Graduate Institute of Pharmacognosy, Taipei Medical University, Taipei 11031, Taiwan. khchuang@tmu.edu.tw.
authors: Kuo-Hsiang
authors: KH
authors: Chuang
authors: Department of Biological Science and Technology, National Chiao Tung University, Hsinchu 30050, Taiwan. sctzou@gmail.com.
authors: Shey-Cherng
authors: SC
authors: Tzou
authors: School of Pharmacy, China Medical University, Taichung 40402, Taiwan. cschen7@mail.cmu.edu.tw.
authors: Chien-Shu
authors: CS
authors: Chen
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites; D045744:Cell Line, Tumor; D003198:Computer Simulation; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt
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