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

Min Wu Chao, Tony Eight Lin, Wei Chun HuangFu, Chao Di Chang, Huang Ju Tu, Liang Chieh Chen, Shih Chung Yen, Tzu Ying Sung, Wei Jan Huang, Chia Ron Yang, Shiow Lin Pan, Kai Cheng Hsu

研究成果: 雜誌貢獻文章同行評審

摘要

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.
原文英語
頁(從 - 到)98-108
頁數11
期刊Journal of Enzyme Inhibition and Medicinal Chemistry
36
發行號1
DOIs
出版狀態已發佈 - 十二月 2021

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery

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