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Identification of a dual TAOK1 and MAP4K5 inhibitor using a structure-based virtual screening approach.
Chao, Min-Wu; Lin, Tony Eight; HuangFu, Wei-Chun; Chang, Chao-Di; Tu, Huang-Ju; Chen, Liang-Chieh; Yen, Shih-Chung; Sung, Tzu-Ying; Huang, Wei-Jan; Yang, Chia-Ron; Pan, Shiow-Lin; Hsu, Kai-Cheng.
Afiliação
  • Chao MW; Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
  • Lin TE; School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan.
  • HuangFu WC; Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
  • Chang CD; Master Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
  • Tu HJ; Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
  • Chen LC; Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
  • Yen SC; Ph.D. Program in Biotechnology Research and Development, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
  • Sung TY; TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan.
  • Huang WJ; Ph.D. Program in Biotechnology Research and Development, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
  • Yang CR; Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
  • Pan SL; School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan.
  • Hsu KC; Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
J Enzyme Inhib Med Chem ; 36(1): 98-108, 2021 Dec.
Article em En | MEDLINE | ID: mdl-33167727
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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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proteínas Serina-Treonina Quinases / Inibidores de Proteínas Quinases / Antineoplásicos Tipo de estudo: Diagnostic_studies / Screening_studies Idioma: En Revista: J Enzyme Inhib Med Chem Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Taiwan

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proteínas Serina-Treonina Quinases / Inibidores de Proteínas Quinases / Antineoplásicos Tipo de estudo: Diagnostic_studies / Screening_studies Idioma: En Revista: J Enzyme Inhib Med Chem Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Taiwan