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 Chem Neurosci. 2012 Nov 21;3(11):857-72. doi: 10.1021/cn300094k. Epub 2012 Aug 28.


With 24.3 million people affected in 2005 and an estimated rise to 42.3 million in 2020, dementia is currently a leading unmet medical need and costly burden on public health. Seventy percent of these cases have been attributed to Alzheimer's disease (AD), a neurodegenerative pathology whose most evident symptom is a progressive decline in cognitive functions. Dual specificity tyrosine phosphorylation regulated kinase-1A (DYRK1A) is important in neuronal development and plays a variety of functional roles within the adult central nervous system. The DYRK1A gene is located within the Down syndrome critical region (DSCR) on human chromosome 21 and current research suggests that overexpression of DYRK1A may be a significant factor leading to cognitive deficits in people with Alzheimer's disease (AD) and Down syndrome (DS). Currently, treatment options for cognitive deficiencies associated with Down syndrome, as well as Alzheimer's disease, are extremely limited and represent a major unmet therapeutic need. Small molecule inhibition of DYRK1A activity in the brain may provide an avenue for pharmaceutical intervention of mental impairment associated with AD and other neurodegenerative diseases. We herein review the current state of the art in the development of DYRK1A inhibitors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism*
  • Animals
  • Anthraquinones / pharmacology
  • Biomedical Research*
  • Carbolines / pharmacology
  • Catechin / analogs & derivatives
  • Catechin / pharmacology
  • Chromosomes, Human, Pair 21 / genetics
  • Chromosomes, Human, Pair 21 / metabolism
  • Coumarins / pharmacology
  • Down Syndrome / genetics
  • Down Syndrome / metabolism
  • Drug Design*
  • Dyrk Kinases
  • Humans
  • Mice
  • Protein Kinase Inhibitors / pharmacology
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein Serine-Threonine Kinases / metabolism
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / metabolism
  • tau Proteins / metabolism


  • Anthraquinones
  • Carbolines
  • Coumarins
  • Protein Kinase Inhibitors
  • tau Proteins
  • 1,2,5,8-tetrahydroxy anthraquinone
  • Catechin
  • coumarin
  • epigallocatechin gallate
  • Protein-Tyrosine Kinases
  • Protein Serine-Threonine Kinases