https://scholars.lib.ntu.edu.tw/handle/123456789/565262
標題: | Identification of a dual TAOK1 and MAP4K5 inhibitor using a structure-based virtual screening approach | 作者: | Chao M.-W. Lin T.E. HuangFu W.-C. Chang C.-D. Tu H.-J. Chen L.-C. Yen S.-C. Sung T.-Y. Huang W.-J. CHIA-RON YANG Pan S.-L. Hsu K.-C. |
關鍵字: | cancer; drug discovery; kinase inhibitor; small-molecule; STE20 pathway; Structure-based virtual screening | 公開日期: | 2021 | 卷: | 36 | 期: | 1 | 起(迄)頁: | 98-108 | 來源出版物: | Journal of Enzyme Inhibition and Medicinal Chemistry | 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. ? 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-85095776883&doi=10.1080%2f14756366.2020.1843452&partnerID=40&md5=1546f6942d20a29ded286cdb6b94795f https://scholars.lib.ntu.edu.tw/handle/123456789/565262 |
ISSN: | 14756366 | DOI: | 10.1080/14756366.2020.1843452 | SDG/關鍵字: | antineoplastic agent; axitinib; dasatinib; gefitinib; imatinib; kinase homologous to ste20; palbociclib; pazopanib; protein serine threonine kinase; protein serine threonine kinase inhibitor; sunitinib; thousand and one amino acid kinase; unclassified drug; antineoplastic agent; MAP4K5 protein, human; protein kinase inhibitor; protein serine threonine kinase; TAO1 protein kinase; antineoplastic activity; antiproliferative activity; apoptosis; Article; cancer growth; cell cycle G1 phase; cell cycle progression; cell proliferation; cell survival; cell viability; colorectal cancer; controlled study; crystal structure; drug binding site; drug identification; drug protein binding; drug purity; drug screening; drug selectivity; drug targeting; enzyme inhibition; flow cytometry; fluorescence resonance energy transfer; high performance liquid chromatography; high throughput screening; human; human cell; hydrogen bond; IC50; in vitro study; in vivo study; molecular docking; molecular weight; non small cell lung cancer; percentage of cells in G0/G1 phase; priority journal; structure activity relation; cell cycle; chemical structure; chemistry; dose response; drug effect; drug screening; metabolism; preclinical study; structure activity relation; synthesis; tumor cell culture; Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Screening Assays, Antitumor; Humans; Molecular Structure; Protein Kinase Inhibitors; Protein-Serine-Threonine Kinases; Structure-Activity Relationship; Tumor Cells, Cultured |
顯示於: | 藥學系 |
在 IR 系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。