Comparative Efficacy and Selectivity of Pharmacological Inhibitors of DYRK and CLK Protein Kinases

Dual-specificity, tyrosine phosphorylation-regulated
kinases (DYRKs)
and cdc2-like kinases (CLKs) play a large variety of cellular functions
and are involved in several diseases (cognitive disorders, diabetes,
cancers, etc.). There is, thus, growing interest in pharmacological
inhibitors as chemical probes and potential drug candidates. This
study presents an unbiased evaluation of the kinase inhibitory activity
of a library of 56 reported DYRK/CLK inhibitors on the basis of comparative,
side-by-side, catalytic activity assays on a panel of 12 recombinant
human kinases, enzyme kinetics (residence time and Kd), in-cell inhibition of Thr-212-Tau phosphorylation,
and cytotoxicity. The 26 most active inhibitors were modeled in the
crystal structure of DYRK1A. The results show a rather large diversity
of potencies and selectivities among the reported inhibitors and emphasize
the difficulties to avoid “off-targets” in this area
of the kinome. The use of a panel of DYRKs/CLKs inhibitors is suggested
to analyze the functions of these kinases in cellular processes.