Molecules (Jan 2018)

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

  • Rosanna Meine,
  • Walter Becker,
  • Hannes Falke,
  • Lutz Preu,
  • Nadège Loaëc,
  • Laurent Meijer,
  • Conrad Kunick

DOI
https://doi.org/10.3390/molecules23020064
Journal volume & issue
Vol. 23, no. 2
p. 64

Abstract

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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.

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