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Molecules. 2018 Jan 24;23(2). pii: E64. doi: 10.3390/molecules23020064.

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

Author information

1
Institut für Medizinische und Pharmazeutische Chemie, Technische Universität Braunschweig, Beethovenstraße 55, 38106 Braunschweig, Germany. r.meine@tu-bs.de.
2
Zentrum für Pharmaverfahrenstechnik (PVZ), Technische Universität Braunschweig, Franz-Liszt-Straße 35A, 38106 Braunschweig, Germany. r.meine@tu-bs.de.
3
Institute of Pharmacology and Toxicology, Medical Faculty of the RWTH Aachen University, Wendlingweg 2, 52074 Aachen, Germany. wbecker@ukaachen.de.
4
Institut für Medizinische und Pharmazeutische Chemie, Technische Universität Braunschweig, Beethovenstraße 55, 38106 Braunschweig, Germany. h.falke@tu-braunschweig.de.
5
Institut für Medizinische und Pharmazeutische Chemie, Technische Universität Braunschweig, Beethovenstraße 55, 38106 Braunschweig, Germany. l.preu@tu-bs.de.
6
ManRos Therapeutics, Perharidy Research Center, 29680 Roscoff, France. nadege.loaec@univ-brest.fr.
7
ManRos Therapeutics, Perharidy Research Center, 29680 Roscoff, France. meijer@manros-therapeutics.com.
8
Institut für Medizinische und Pharmazeutische Chemie, Technische Universität Braunschweig, Beethovenstraße 55, 38106 Braunschweig, Germany. c.kunick@tu-bs.de.
9
Zentrum für Pharmaverfahrenstechnik (PVZ), Technische Universität Braunschweig, Franz-Liszt-Straße 35A, 38106 Braunschweig, Germany. c.kunick@tu-bs.de.

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.

KEYWORDS:

DYRK1A; fraction of saturation; fragment-based drug development; indole; lipophilicity; molecular docking; protein kinase inhibitor; solubility

PMID:
29364148
PMCID:
PMC6017736
DOI:
10.3390/molecules23020064
[Indexed for MEDLINE]
Free PMC Article

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