A broad activity screen in support of a chemogenomic map for kinase signalling research and drug discovery

Biochem J. 2013 Apr 15;451(2):313-28. doi: 10.1042/BJ20121418.


Despite the development of a number of efficacious kinase inhibitors, the strategies for rational design of these compounds have been limited by target promiscuity. In an effort to better understand the nature of kinase inhibition across the kinome, especially as it relates to off-target effects, we screened a well-defined collection of kinase inhibitors using biochemical assays for inhibitory activity against 234 active human kinases and kinase complexes, representing all branches of the kinome tree. For our study we employed 158 small molecules initially identified in the literature as potent and specific inhibitors of kinases important as therapeutic targets and/or signal transduction regulators. Hierarchical clustering of these benchmark kinase inhibitors on the basis of their kinome activity profiles illustrates how they relate to chemical structure similarities and provides new insights into inhibitor specificity and potential applications for probing new targets. Using this broad dataset, we provide a framework for assessing polypharmacology. We not only discover likely off-target inhibitor activities and recommend specific inhibitors for existing targets, but also identify potential new uses for known small molecules.

MeSH terms

  • Aurora Kinases
  • Cluster Analysis
  • Drug Design
  • Drug Discovery / methods*
  • Drug Evaluation, Preclinical / methods*
  • ErbB Receptors / antagonists & inhibitors
  • Humans
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors
  • MAP Kinase Kinase 4 / antagonists & inhibitors
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinases / genetics
  • Protein Kinases / metabolism*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Receptors, Vascular Endothelial Growth Factor / antagonists & inhibitors
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Reproducibility of Results
  • Signal Transduction / drug effects
  • Small Molecule Libraries
  • Structure-Activity Relationship
  • Syk Kinase
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors


  • Intracellular Signaling Peptides and Proteins
  • Protein Kinase Inhibitors
  • Recombinant Proteins
  • Small Molecule Libraries
  • Protein Kinases
  • EGFR protein, human
  • ErbB Receptors
  • Protein-Tyrosine Kinases
  • Receptors, Vascular Endothelial Growth Factor
  • SYK protein, human
  • Syk Kinase
  • Aurora Kinases
  • Protein Serine-Threonine Kinases
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 4