Abstract
Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a potential drug target because of its role in the development of Down syndrome and Alzheimer’s disease. The selective DYRK1A inhibitor 10-iodo-11H-indolo[3,2-c]quinoline-6-carboxylic acid (KuFal194), a large, flat and lipophilic molecule, suffers from poor water solubility, limiting its use as chemical probe in cellular assays and animal models. Based on the structure of KuFal194, 7-chloro-1H-indole-3-carbonitrile was selected as fragment template for the development of smaller and less lipophilic DYRK1A inhibitors. By modification of this fragment, a series of indole-3-carbonitriles was designed and evaluated as potential DYRK1A ligands by molecular docking studies. Synthesis and in vitro assays on DYRK1A and related protein kinases identified novel double-digit nanomolar inhibitors with submicromolar activity in cell culture assays.
Highlights
Protein kinases are enzymes catalyzing the transfer of γ-phosphate from ATP to the hydroxyl group of serine, threonine or tyrosine residues of their substrates
Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) activity is associated with Down syndrome (DS) and Alzheimer’s disease (AD) [3,4]
The starting materials and reagents were purchased from Acros Organics (Geel, Belgium), Alfa Aesar (Karlsruhe, Germany) and Sigma-Aldrich (Steinheim, Germany). 7-Chloroindole was purchased from Activate Scientific (Prien, Germany), 7-bromoindole was purchased from Maybridge (Loughborough, United Kingdom)
Summary
Protein kinases are enzymes catalyzing the transfer of γ-phosphate from ATP to the hydroxyl group of serine, threonine or tyrosine residues of their substrates. Since these substrates affect important cellular processes such as differentiation, cell cycle regulation, proliferation and apoptosis, the dysregulation of protein kinases is involved in numerous human diseases, e.g., cancer, diabetes, inflammatory or neurodegenerative disorders [1]. Because DYRK1A plays an important role for the regulation of proliferation and differentiation of neuronal cells, its overexpression was suspected to be linked to DS symptoms such as mental retardation and Molecules 2018, 23, 64; doi:10.3390/molecules23020064 www.mdpi.com/journal/molecules
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