Journal of Microbiology and Biotechnology

The Korean Society for Microbiology and Biotechnology (한국미생물·생명공학회)
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Regulation of AKT Activity by Inhibition of the Pleckstrin Homology Domain-PtdIns(3,4,5)P3 Interaction Using Flavonoids

  • Kang, Yerin (Department of Environmental Health Science, Konkuk University) ;
  • Jang, Geupil (Department of Agricultural Biotechnology and Research Institute of Agriculture and Life Sciences, Seoul National University) ;
  • Ahn, Seunghyun (Division of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University) ;
  • Lee, Youngshim (Division of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University) ;
  • Shin, Soon Young (Department of Biological Sciences, Sanghuh College of Life Sciences, Konkuk University) ;
  • Yoon, Youngdae (Department of Environmental Health Science, Konkuk University)
  • Received : 2018.05.02
  • Accepted : 2018.07.03
  • Published : 2018.08.28
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Abstract

The 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 lipid-binding domain of AKT, rather than the catalytic kinase domain, in anticancer drug development.

Keywords

References

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