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Open AccessArticle

Indole-3-Carbonitriles as DYRK1A Inhibitors by Fragment-Based Drug Design

1
Institut für Medizinische und Pharmazeutische Chemie, Technische Universität Braunschweig, Beethovenstraße 55, 38106 Braunschweig, Germany
2
Zentrum für Pharmaverfahrenstechnik (PVZ), Technische Universität Braunschweig, Franz-Liszt-Straße 35A, 38106 Braunschweig, Germany
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Institute of Pharmacology and Toxicology, Medical Faculty of the RWTH Aachen University, Wendlingweg 2, 52074 Aachen, Germany
4
ManRos Therapeutics, Perharidy Research Center, 29680 Roscoff, France
*
Author to whom correspondence should be addressed.
Molecules 2018, 23(2), 64; https://doi.org/10.3390/molecules23020064
Received: 22 December 2017 / Revised: 11 January 2018 / Accepted: 12 January 2018 / Published: 24 January 2018
(This article belongs to the Section Medicinal Chemistry)
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. View Full-Text
Keywords: DYRK1A; fraction of saturation; fragment-based drug development; indole; lipophilicity; molecular docking; protein kinase inhibitor; solubility DYRK1A; fraction of saturation; fragment-based drug development; indole; lipophilicity; molecular docking; protein kinase inhibitor; solubility
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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.

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