DYRK1A kinase inhibition with emphasis on neurodegeneration: A comprehensive evolution story-cum-perspective

Eur J Med Chem. 2018 Oct 5:158:559-592. doi: 10.1016/j.ejmech.2018.08.093. Epub 2018 Sep 11.

Abstract

Alzheimer, the fourth leading cause of death embodies a key responsible event including formation of β-amyloid protein clustering to amyloid plaque on blood vessels. The origin of above events is Amyloid precursor protein (APP) which is an integral membrane protein known for its function in synapses formation. Modern research had proposed that the over expression of DYRK1A (Dual specificity tyrosine phosphorylation regulated kinase1A, a family of protein kinases, positioned within the Down's syndrome critical region (DSCR) on human chromosome 21causes phosphorylation of APP protein resulting in its cleavage to Aβ 40, 42 and tau proteins (regulated by beta and gamma secretase) which plays critical role in early onset of Alzheimer's disease (AD) detected in Down's syndrome (DS), leading to permanent functional and structural deformities which results ultimately into neuro-degeneration and neuronal death. Therefore, DYRK1A emerges as a potential target for prevention of neuro-degeneration and hence Alzheimer. Presently, the treatment methods for Down's syndrome, as well as Alzheimer's disease are extremely biased and represent a major deficiency for therapeutic necessities. We hereby, focus our review on the current status of the research and contributions in the development of DYRK1A inhibitors.

Keywords: Amyloid precursor protein; DYRK1A; Down's syndrome critical region (DSCR) Alzheimer's disease; Neurodegeneration.

Publication types

  • Review

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / physiopathology
  • Animals
  • Computer-Aided Design
  • Down Syndrome / drug therapy*
  • Down Syndrome / metabolism
  • Down Syndrome / physiopathology
  • Drug Discovery / methods*
  • Dyrk Kinases
  • Humans
  • Molecular Targeted Therapy / methods
  • Neurogenesis / drug effects
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein Serine-Threonine Kinases / metabolism
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / metabolism

Substances

  • Protein Kinase Inhibitors
  • Protein-Tyrosine Kinases
  • Protein Serine-Threonine Kinases

Supplementary concepts

  • Down Syndrome Critical Region