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Molecules 2018, 23(2), 64; doi:10.3390/molecules23020064

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

Institut für Medizinische und Pharmazeutische Chemie, Technische Universität Braunschweig, Beethovenstraße 55, 38106 Braunschweig, Germany
Zentrum für Pharmaverfahrenstechnik (PVZ), Technische Universität Braunschweig, Franz-Liszt-Straße 35A, 38106 Braunschweig, Germany
Institute of Pharmacology and Toxicology, Medical Faculty of the RWTH Aachen University, Wendlingweg 2, 52074 Aachen, Germany
ManRos Therapeutics, Perharidy Research Center, 29680 Roscoff, France
Author to whom correspondence should be addressed.
Received: 22 December 2017 / Revised: 11 January 2018 / Accepted: 12 January 2018 / Published: 24 January 2018
(This article belongs to the Section Medicinal Chemistry)
View Full-Text   |   Download PDF [3663 KB, uploaded 9 February 2018]   |  


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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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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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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