Abstract
Dual-specificity tyrosine-regulated kinase 1 A (DYRK1A) is crucial in neurogenesis, synaptogenesis, and neuronal functions. Its dysregulation is linked to neurodegenerative disorders like Down syndrome and Alzheimer's disease. Although the development of DYRK1A inhibitors has significantly advanced in recent years, the selectivity of these drugs remains a critical challenge, potentially impeding further progress. In this study, we utilised structure-based virtual screening (SBVS) from NCI library to discover novel DYRK1A inhibitors. The top-ranked compounds were then validated through enzymatic assays to assess their efficacy towards DYRK1A. Among them, NSC361563 emerged as a potent and selective DYRK1A inhibitor. It was shown to decrease tau phosphorylation at multiple sites, thereby enhancing tubulin stability. Moreover, NSC361563 diminished the formation of amyloid β and offered neuroprotective benefits against amyloid β-induced toxicity. Our research highlights the critical role of selective DYRK1A inhibitors in treating neurodegenerative diseases and presents a promising starting point for the development of targeted therapies.
Keywords:
Aβ; DYRK1A; Tau; structure-based virtual screening.
MeSH terms
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Amyloid beta-Peptides* / antagonists & inhibitors
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Amyloid beta-Peptides* / metabolism
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Animals
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Dose-Response Relationship, Drug*
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Drug Discovery
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Dyrk Kinases*
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Humans
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Molecular Structure
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Neuroprotective Agents / chemical synthesis
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Neuroprotective Agents / chemistry
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Neuroprotective Agents / pharmacology
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Phosphorylation / drug effects
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Protein Kinase Inhibitors* / chemical synthesis
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Protein Kinase Inhibitors* / chemistry
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Protein Kinase Inhibitors* / pharmacology
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Protein Serine-Threonine Kinases* / antagonists & inhibitors
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Protein Serine-Threonine Kinases* / metabolism
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Protein-Tyrosine Kinases* / antagonists & inhibitors
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Protein-Tyrosine Kinases* / metabolism
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Structure-Activity Relationship
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tau Proteins* / antagonists & inhibitors
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tau Proteins* / metabolism
Substances
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Dyrk Kinases
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Protein-Tyrosine Kinases
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Protein Serine-Threonine Kinases
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tau Proteins
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Protein Kinase Inhibitors
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Amyloid beta-Peptides
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Neuroprotective Agents
Grants and funding
We acknowledge support from the Ministry of Science and Technology (MOST 110–2320-B-038–040-MY3, MOST 112-2320-B-038–052, and MOST 113-2320-B-038-010). This research was also partially supported by the “TMU Research Centre of Cancer Translational Medicine” from the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan. This work was also supported by National Science and Technology Council.