Focused screening to identify new adenosine kinase inhibitors

Bioorg Med Chem. 2016 Nov 1;24(21):5127-5133. doi: 10.1016/j.bmc.2016.08.026. Epub 2016 Aug 21.

Abstract

Adenosine kinase (AdK) is a key player in controlling intra- and extracellular concentrations of the signaling molecule adenosine. Extensive evidence points to an important role of AdK in several diseases, and suggests that AdK inhibition might be a promising therapeutic strategy. The development of a new AdK assay and subsequent screening of part of our focused compound library led to the identification of 12 hit compounds (hit rate of 6%) representing six new classes of non-nucleoside human AdK inhibitors. The most potent inhibitor 1 displayed a Ki value of 184nM. Compound screening with a newly developed assay was useful and efficient for discovering novel AdK inhibitors which may serve as lead structures for developing drugs for adenosine augmentation therapy.

Keywords: Adenosine homeostasis; Adenosine kinase assay; Adenosine kinase inhibitors; Compound library; High-throughput screening.

MeSH terms

  • Adenosine Kinase / antagonists & inhibitors*
  • Adenosine Kinase / metabolism
  • Dose-Response Relationship, Drug
  • Humans
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

  • Protein Kinase Inhibitors
  • Adenosine Kinase