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Research articleMolecular and Cellular Microbiology (MCM) | Biochemistry and Physiology
Regulation of AKT Activity by Inhibition of the Pleckstrin Homology Domain-PtdIns(3,4,5)P3 Interaction Using Flavonoids
1Department of Environmental Health Science, Konkuk University, Seoul 05029, Republic of Korea, 2Department of Agricultural Biotechnology and Research Institute of Agriculture and Life Sciences, Seoul National University, Seoul 08826, Republic of Korea, 3Division of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Seoul 05029, Republic of Korea, 4Department of Biological Sciences, Sanghuh College of Life Sciences, Konkuk University, Seoul 05029, Republic of KoreaReceived: May 2, 2018; Accepted: July 3, 2018
J. Microbiol. Biotechnol. 2018; 28(8): 1401-1411
Published August 28, 2018
Copyright © The Korean Society for Microbiology and Biotechnology.
AbstractThe serine-threonine kinase AKT plays a pivotal role in tumor progression and is frequently overactivated in cancer cells; this protein is therefore a critical therapeutic target for cancer intervention. We aimed to identify small molecule inhibitors of the pleckstrin homology (PH) domain of AKT to disrupt binding of phosphatidylinositol-3,4,5-trisphosphate (PIP3), thereby downregulating AKT activity. Liposome pulldown assays coupled with fluorescence spectrometry were used to screen flavonoids for inhibition of the AKT PH-PIP3 interaction. Western blotting was used to determine the effects of the inhibitors on AKT activation in cancer cells, and in silico docking was used for structural analysis and optimization of inhibitor structure. Several flavonoids showing up to 50% inhibition of the AKT PH-PIP3 interaction decreased the level of AKT activation at the cellular level. In addition, the modified flavonoid showed increased inhibitory effects and the approach would be applied to develop anticancer drug candidates. In this study, we provide a rationale for targeting the lipidbinding domain of AKT, rather than the catalytic kinase domain, in anticancer drug development.
KeywordsPtdIns(3,4,5)P3, pleckstrin homology (PH) domain, AKT, flavonoid, in silico docking