title: DYRK1A inhibition as potential treatment for Alzheimer's disease.
abstract: In total, 47,500,000 people worldwide are affected by dementia and this number is estimated to double by 2030 and triple within 2050 resulting in a huge burden on public health. Alzheimer's disease (AD), a progressive neurodegenerative disorder, is the most common cause of dementia, accounting for 60-70% of all the cases. The cause of AD is still poorly understood but several brain abnormalities (e.g., loss of neuronal connections and neuronal death) have been identified in affected patients. In addition to the accumulation of β-amyloid plaques in the brain tissue, aberrant phosphorylation of tau proteins has proved to increase neuronal death. DYRK1A phosphorylates tau on 11 different Ser/Thr residues, resulting in the formation of aggregates called 'neurofibrillary tangles' which, together with amyloid plaques, could be responsible for dementia, neuronal degeneration and cell death. Small molecule inhibition of DYRK1A could thus represent an interesting approach toward the treatment of Alzheimer's and other neurodegenerative diseases. Herein we review the current progress in the identification and development of DYRK1A inhibitors.
authors.affiliation: Medicinal Chemistry, Taros Chemicals GmbH & Co. KG, Emil-Figge-Str. 76a, 44227 Dortmund, Germany.
authors.forename: Silvia
authors.initials: S
authors.lastname: Stotani
authors.affiliation: Medicinal Chemistry, Taros Chemicals GmbH & Co. KG, Emil-Figge-Str. 76a, 44227 Dortmund, Germany.|DE Shaw Research, 120W 45th Street, New York, NY 10036, USA.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Giordanetto
authors.affiliation: Medicinal Chemistry, Taros Chemicals GmbH & Co. KG, Emil-Figge-Str. 76a, 44227 Dortmund, Germany.
authors.forename: Federico
authors.initials: F
authors.lastname: Medda
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016923:Cell Death; D055808:Drug Discovery; D006801:Humans; D009474:Neurons / Q000473:pathology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D016875:tau Proteins / Q000378:metabolism; D000097603:Dyrk Kinases
chemical_list: D016229:Amyloid beta-Peptides; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D016875:tau Proteins; D000097603:Dyrk Kinases
keywords: Alzheimer’s disease; DYRK1A; dementia; neurofibrillary tangles; small-molecule inhibitors; β-amyloid plaques