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Identification of a dual TAOK1 and MAP4K5 inhibitor using a structure-based virtual screening approach.

Authors
  • Chao, Min-Wu1, 2
  • Lin, Tony Eight1, 3
  • HuangFu, Wei-Chun1, 4, 5, 6
  • Chang, Chao-Di5
  • Tu, Huang-Ju1, 2
  • Chen, Liang-Chieh1, 7
  • Yen, Shih-Chung7, 8
  • Sung, Tzu-Ying9
  • Huang, Wei-Jan5, 10, 11
  • Yang, Chia-Ron2
  • Pan, Shiow-Lin1, 4, 5, 6, 12
  • Hsu, Kai-Cheng1, 4, 5, 6, 12, 13
  • 1 Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan. , (Taiwan)
  • 2 School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan. , (Taiwan)
  • 3 Master Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan. , (Taiwan)
  • 4 Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan. , (Taiwan)
  • 5 Ph.D. Program in Biotechnology Research and Development, College of Pharmacy, Taipei Medical University, Taipei, Taiwan. , (Taiwan)
  • 6 TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan. , (Taiwan)
  • 7 Warshel Institute for Computational Biology, The Chinese University of Hong Kong, Shenzhen, P. R. China. , (China)
  • 8 School of Life and Health Sciences, The Chinese University of Hong Kong, Shenzhen, P. R. China. , (China)
  • 9 Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsinchu, Taiwan. , (Taiwan)
  • 10 School of Pharmacy, Taipei Medical University, Taipei, Taiwan. , (Taiwan)
  • 11 Graduate Institute of Pharmacognosy, Taipei Medical University, Taipei, Taiwan. , (Taiwan)
  • 12 Biomedical Commercialization Center, Taipei Medical University, Taipei, Taiwan. , (Taiwan)
  • 13 Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan. , (Taiwan)
Type
Published Article
Journal
Journal of Enzyme Inhibition and Medicinal Chemistry
Publisher
Informa UK (Taylor & Francis)
Publication Date
Dec 01, 2021
Volume
36
Issue
1
Pages
98–108
Identifiers
DOI: 10.1080/14756366.2020.1843452
PMID: 33167727
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

The STE20 kinase family is a complex signalling cascade that regulates cytoskeletal organisation and modulates the stress response. This signalling cascade includes various kinase mediators, such as TAOK1 and MAP4K5. The dysregulation of the STE20 kinase pathway is linked with cancer malignancy. A small-molecule inhibitor targeting the STE20 kinase pathway has therapeutic potential. In this study, a structure-based virtual screening (SBVS) approach was used to identify potential dual TAOK1 and MAP4K5 inhibitors. Enzymatic assays confirmed three potential dual inhibitors (>50% inhibition) from our virtual screening, and analysis of the TAOK1 and MAP4K5 binding sites indicated common interactions for dual inhibition. Compound 1 revealed potent inhibition of colorectal and lung cancer cell lines. Furthermore, compound 1 arrested cancer cells in the G0/G1 phase, which suggests the induction of apoptosis. Altogether, we show that the STE20 signalling mediators TAOK1 and MAP4K5 are promising targets for drug research.

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