Structure-Guided Discovery of Potent and Selective DYRK1A Inhibitors

J Med Chem. 2021 May 27;64(10):6745-6764. doi: 10.1021/acs.jmedchem.1c00023. Epub 2021 May 12.

Abstract

The kinase DYRK1A is an attractive target for drug discovery programs due to its implication in multiple diseases. Through a fragment screen, we identified a simple biaryl compound that is bound to the DYRK1A ATP site with very high efficiency, although with limited selectivity. Structure-guided optimization cycles enabled us to convert this fragment hit into potent and selective DYRK1A inhibitors. Exploiting the structural differences in DYRK1A and its close homologue DYRK2, we were able to fine-tune the selectivity of our inhibitors. Our best compounds potently inhibited DYRK1A in the cell culture and in vivo and demonstrated drug-like properties. The inhibition of DYRK1A in vivo translated into dose-dependent tumor growth inhibition in a model of ovarian carcinoma.

MeSH terms

  • Adenosine Triphosphate / chemistry
  • Animals
  • Binding Sites
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cyclin-Dependent Kinase 9 / antagonists & inhibitors
  • Cyclin-Dependent Kinase 9 / metabolism
  • Drug Design*
  • Drug Evaluation, Preclinical
  • Female
  • Humans
  • Mice
  • Mice, Nude
  • Molecular Docking Simulation
  • Ovarian Neoplasms / drug therapy
  • Ovarian Neoplasms / pathology
  • Phosphorylation / drug effects
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / metabolism
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein Serine-Threonine Kinases / metabolism
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / metabolism
  • Pyrimidines / chemistry
  • Pyrimidines / metabolism
  • Pyrimidines / pharmacology
  • Pyrimidines / therapeutic use
  • Structure-Activity Relationship

Substances

  • Protein Isoforms
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Adenosine Triphosphate
  • Dyrk kinase
  • Protein-Tyrosine Kinases
  • Protein Serine-Threonine Kinases
  • Cyclin-Dependent Kinase 9