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

Molecules. 2018 Jan 24;23(2):64. doi: 10.3390/molecules23020064.


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.

MeSH terms

  • Drug Design*
  • Enzyme Activation / drug effects
  • Indoles / chemistry*
  • Inhibitory Concentration 50
  • Molecular Conformation
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Molecular Structure
  • Nitriles / chemical synthesis
  • Nitriles / chemistry*
  • Nitriles / pharmacology*
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / chemistry
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / chemistry
  • Solubility


  • Indoles
  • Nitriles
  • Protein Kinase Inhibitors
  • indole
  • Dyrk kinase
  • Protein-Tyrosine Kinases
  • Protein-Serine-Threonine Kinases