A novel DYRK1A (dual specificity tyrosine phosphorylation-regulated kinase 1A) inhibitor for the treatment of Alzheimer's disease: effect on Tau and amyloid pathologies in vitro

Topic: Brain proteins, microglia and lab models

The dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) gene is located within the Down Syndrome (DS) critical region on chromosome 21 and is implicated in the generation of Tau and amyloid pathologies that are associated with the early onset Alzheimer's Disease (AD) observed in DS. DYRK1A is also found associated with neurofibrillary tangles in sporadic AD and phosphorylates key AD players (Tau, amyloid precursor, protein, etc). Thus, DYRK1A may be an important therapeutic target to modify the course of Tau and amyloid beta (Aβ) pathologies. Here, we describe EHT 5372 (methyl 9-(2,4-dichlorophenylamino) thiazolo[5,4-f]quinazoline-2-carbimidate), a novel, highly potent (IC50 = 0.22 nM) DYRK1A inhibitor with a high degree of selectivity over 339 kinases. Models in which inhibition of DYRK1A by siRNA reduced and DYRK1A over-expression induced Tau phosphorylation or Aβ production were used. EHT 5372 inhibits DYRK1A-induced Tau phosphorylation at multiple AD-relevant sites in biochemical and cellular assays. EHT 5372 also normalizes both Aβ-induced Tau phosphorylation and DYRK1A-stimulated Aβ production. DYRK1A is thus as a key element of Aβ-mediated Tau hyperphosphorylation, which links Tau and amyloid pathologies. EHT 5372 and other compounds in its class warrant in vivo investigation as a novel, high-potential therapy for AD and other Tau opathies. Inhibition of the dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) is a new high-potential therapeutic approach for Alzheimer disease. Here we describe EHT 5372, a novel potent and selective DYRK1A inhibitor. EHT 5372 inhibits DYRK1A-induced Tau phosphorylation, Aβ production and Aβ effects on phospho-Tau, including Tau aggregation.

Key findings

• The dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) gene is located within the Down Syndrome (DS) critical region on chromosome 21 and is implicated in the generation of Tau and amyloid pathologies that are associated with the early onset Alzheimer's Disease (AD) observed in DS.
• DYRK1A is also found associated with neurofibrillary tangles in sporadic AD and phosphorylates key AD players (Tau, amyloid precursor, protein, etc).

Why it matters

A new compound, EHT 5372, blocks the DYRK1A enzyme and reduces tau phosphorylation and amyloid beta production in laboratory cell and biochemical assays. These are in vitro results only, and the authors say the compound and its class need testing in living animals before any therapy for Alzheimer's disease can be considered.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1111/jnc.13018
• PubMed: 25556849
• Original source →

May need a subscription OpenAlex found no free copy of the full text (checked 6 Feb 1020), so the publisher may charge for it. The PubMed abstract is free.

@article{coutadeur2015-25556849,
  author  = {Coutadeur, S. and Benyamine, H. and Delalonde, L. and de Oliveira, C. and Leblond, B. and Foucourt, A. and Besson, T. and Casagrande, A. S. and others},
  title   = {{A novel DYRK1A (dual specificity tyrosine phosphorylation-regulated kinase 1A) inhibitor for the treatment of Alzheimer's disease: effect on Tau and amyloid pathologies in vitro}},
  journal = {Journal of neurochemistry},
  year    = {2015},
  doi     = {10.1111/jnc.13018},
  pmid    = {25556849},
  url     = {https://doi.org/10.1111/jnc.13018}
}

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here.

• Neuropathological stageing of Alzheimer-related changes Acta Neuropathologica · 1991-09-01 · usefulness score 58/100 · Brain tissue and pathology
• The DYRK1A gene, encoded in chromosome 21 Down syndrome critical region, bridges between beta-amyloid production and tau phosphorylation in Alzheimer disease Human molecular genetics · 2006-11-29 · usefulness score 49/100 · Genetics
• DYRK1A-mediated hyperphosphorylation of Tau. A functional link between Down syndrome and Alzheimer disease The Journal of biological chemistry · 2007-09-28 · usefulness score 46/100 · Down syndrome and Alzheimer's
• Increased dosage of Dyrk1A alters alternative splicing factor (ASF)-regulated alternative splicing of tau in Down syndrome The Journal of biological chemistry · 2008-07-24 · usefulness score 46/100 · Down syndrome and Alzheimer's
• Constitutive Dyrk1A is abnormally expressed in Alzheimer disease, Down syndrome, Pick disease, and related transgenic models Neurobiology of disease · 2005-11-01 · usefulness score 44/100 · Down syndrome and Alzheimer's
• The role of DYRK1A in neurodegenerative diseases The FEBS journal · 2010-12-13 · usefulness score 43/100 · Down syndrome and Alzheimer's
• Etazolate, a neuroprotective drug linking GABA(A) receptor pharmacology to amyloid precursor protein processing Journal of neurochemistry · 2008-07-01 · usefulness score 41/100 · Risk genes beyond APOE

Later studies that cite this one

4 studies in the alzhub library list this one in their references.

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• Design and synthesis of thiazolo[5,4-f]quinazolines as DYRK1A inhibitors, part II Molecules (Basel, Switzerland) · 2014-09-26 · usefulness score 42/100 · Down syndrome and Alzheimer's
• DYRK1A Inhibitors and Perspectives for the Treatment of Alzheimer's Disease Current medicinal chemistry · 2023-01-01 · usefulness score 40/100 · Down syndrome and Alzheimer's
• Dissecting Alzheimer disease in Down syndrome using mouse models Frontiers in behavioral neuroscience · 2015-10-13 · usefulness score 40/100 · Down syndrome and Alzheimer's

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More on Down syndrome and Alzheimer's

• A review that covers this ground Recent advances in the design, synthesis, and biological evaluation of selective DYRK1A inhibitors: a new avenue for a disease modifying treatment of Alzheimer's? ACS chemical neuroscience · 2012-08-28 · usefulness score 36/100
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