Novel Scaffolds for Dual Specificity Tyrosine-Phosphorylation-Regulated Kinase (DYRK1A) Inhibitors

DYRK1A
is one of five members of the dual-specificity tyrosine
(Y) phosphorylation-regulated kinase (DYRK) family. The DYRK1A gene
is located in the Down syndrome critical region and regulates cellular
processes related to proliferation and differentiation of neuronal
progenitor cells during early development. This has focused research
on its role in neuronal degenerative diseases, including Alzheimer’s
and Down syndrome. Recent studies have also shown a possible role
of DYRK1A in diabetes. Here we report a variety of scaffolds not generally
known for DYRK1A inhibition, demonstrating their effects in in vitro assays and
also in cell cultures. These inhibitors effectively block the tau
phosphorylation that is a hallmark of Alzheimer’s disease.
The crystal structures of these inhibitors support the design of optimized
and novel therapeutics.