Dual Specificity, Tyrosine phosphorylation Regulated Kinases (DYRKs) in human disease: the therapeutic potential of pharmacological inhibitors

Phosphorylation represents one of the most common post-translational mechanisms used by cells to regulate their enzymatic and structural proteins. Alterations in protein phosphorylation represent a frequent feature associated with human disease.

Among the 518 human kinases, Dual Specificity, Tyrosine phosphorylation Regulated Kinases (DYRKs) have attracted relatively limited interest despite their key functions in cancer, Alzheimer's disease (AD) and Down syndrome (DS). The DYRK1A kinase gene is located in a specific region of chromosome 21, the „DS critical region“ covering about 33 genes that contribute to the trisomic phenotype. Many observations suggest that moderate (X1.5) DYRK1A overexpression in the brain contributes to the abnormal development observed in DS. Moreover, DYRK1A is likely implicated in AD (many symptoms of which occur systematically and precociously in DS patients when they reach forty years old). DYRK1A phosphorylates both amyloid-β precursor protein (another chromosome 21 gene product...) and Tau protein, two major actors in the development of AD. DYRK1A acts as a priming kinase for GSK-3, another kinase critically involved in both amyloid-β formation and Tau hyperphosphorylation, the two key features of Alzheimer's disease.

During the last few years we have used DYRK1A as a screening target to identify low molecular weight inhibitors of the kinase. From a collection of >15,000 compounds, we have identified a few promising inhibitory scaffolds, most of which are derived from natural products. These molecules inhibit DYRK1A in a cellular context, as revealed by an in vivo reporter system.