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

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.

SUBMITTER: Meine R 

PROVIDER: S-EPMC6017736 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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

Meine Rosanna R   Becker Walter W   Falke Hannes H   Preu Lutz L   Loaëc Nadège N   Meijer Laurent L   Kunick Conrad C  

Molecules (Basel, Switzerland) 20180124 2

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-11<i>H</i>-indolo[3,2-<i>c</i>]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-1<i>H</i>-indole-3  ...[more]

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