Title:DYRK1A Inhibitors and Perspectives for the Treatment of Alzheimer's
Disease
Volume: 30
Issue: 6
Author(s): Márcia Maria de Souza, Arthur Ribeiro Cenci, Kerolain Faoro Teixeira, Valkiria Machado, Majory Christina Garcia Mendes Schuler, Ana Elisa Gonçalves, Ana Paula Dalmagro, Camila André Cazarin, Leonardo Luiz Gomes Ferreira, Aldo Sena de Oliveira and Adriano Defini Andricopulo*
Affiliation:
- Laboratory of Medicinal and Computational Chemistry, Center for Research and Innovation in Biodiversity and Drug Discovery, Institute of Physics of São Carlos, University of São Paulo, São Carlos-SP, Brazil
Keywords:
Alzheimer’s disease, neurodegeneration, protein kinases, enzyme kinetics, DYRK1A inhibitors, molecular docking.
Abstract:
Background: Alzheimer's disease (AD) is a chronic neurodegenerative disease
and the most common form of dementia, especially in the elderly. Due to the increase in
life expectancy, in recent years, there has been an excessive growth in the number of people
affected by this disease, causing serious problems for health systems. In recent years,
research has been intensified to find new therapeutic approaches that prevent the progression
of the disease. In this sense, recent studies indicate that the dual-specificity tyrosine
phosphorylation regulated kinase 1A (DYRK1A) gene, which is located on chromosome
21q22.2 and overexpressed in Down syndrome (DS), may play a significant role in developmental
brain disorders and early onset neurodegeneration, neuronal loss and dementia
in DS and AD. Inhibiting DYRK1A may serve to stop the phenotypic effects of its overexpression
and, therefore, is a potential treatment strategy for the prevention of ageassociated
neurodegeneration, including Alzheimer-type pathology.
Objective: In this review, we investigate the contribution of DYRK1A inhibitors as potential
anti-AD agents.
Methods: A search in the literature to compile an in vitro dataset including IC50 values involving
DYRK1A was performed from 2014 to the present day. In addition, we carried
out structure-activity relationship studies based on in vitro and in silico data.
Results: molecular modeling and enzyme kinetics studies indicate that DYRK1A may
contribute to AD pathology through its proteolytic process, reducing its kinase specificity.
Conclusion: further evaluation of DYRK1A inhibitors may contribute to new therapeutic
approaches for AD.