Indole-3-Carbonitriles as DYRK1A Inhibitors by Fragment-Based Drug Design
AbstractDual-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. View Full-Text
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Meine, R.; Becker, W.; Falke, H.; Preu, L.; Loaëc, N.; Meijer, L.; Kunick, C. Indole-3-Carbonitriles as DYRK1A Inhibitors by Fragment-Based Drug Design. Molecules 2018, 23, 64.
Meine R, Becker W, Falke H, Preu L, Loaëc N, Meijer L, Kunick C. Indole-3-Carbonitriles as DYRK1A Inhibitors by Fragment-Based Drug Design. Molecules. 2018; 23(2):64.Chicago/Turabian Style
Meine, Rosanna; Becker, Walter; Falke, Hannes; Preu, Lutz; Loaëc, Nadège; Meijer, Laurent; Kunick, Conrad. 2018. "Indole-3-Carbonitriles as DYRK1A Inhibitors by Fragment-Based Drug Design." Molecules 23, no. 2: 64.
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