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

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posted on 10.11.2020, 05:10 by 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

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.

Funding

The support was from the Ministry of Science and Technology [MOST 108–2314-B-038–106 and MOST 108–2320-B-038–058-MY3]. This research was also partially supported by the Taiwan Protein Project [Grant No. AS-KPQ-109-TPP2], Health and welfare surcharge of tobacco products [MOHW109-TDU-B-212–134020], "TMU Research Center of Cancer Translational Medicine" from the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan, and the Warshel Institute for Computational Biology with funding from Shenzhen City and Longgang District in the People’s Republic of China.

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