Activity-based kinase profiling of approved tyrosine kinase inhibitors

Genes Cells. 2013 Feb;18(2):110-22. doi: 10.1111/gtc.12022. Epub 2012 Dec 26.


The specificities of nine approved tyrosine kinase inhibitors (imatinib, dasatinib, nilotinib, gefitinib, erlotinib, lapatinib, sorafenib, sunitinib, and pazopanib) were determined by activity-based kinase profiling using a large panel of human recombinant active kinases. This panel consisted of 79 tyrosine kinases, 199 serine/threonine kinases, three lipid kinases, and 29 disease-relevant mutant kinases. Many potential targets of each inhibitor were identified by kinase profiling at the K(m) for ATP. In addition, profiling at a physiological ATP concentration (1 mm) was carried out, and the IC(50) values of the inhibitors against each kinase were compared with the estimated plasma-free concentration (calculated from published pharmacokinetic parameters of plasma C(trough) and C(max) values). This analysis revealed that the approved kinase inhibitors were well optimized for their target kinases. This profiling also implicates activity at particular off-target kinases in drug side effects. Thus, large-scale kinase profiling at both K(m) and physiological ATP concentrations could be useful in characterizing the targets and off-targets of kinase inhibitors.

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Enzyme Activation / drug effects
  • Gene Expression Profiling
  • Humans
  • Inhibitory Concentration 50
  • Kinetics
  • Mutation
  • Phylogeny
  • Protein Binding
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinases / classification
  • Protein Kinases / genetics
  • Protein Kinases / metabolism*
  • Proteome*
  • Reproducibility of Results


  • Protein Kinase Inhibitors
  • Proteome
  • Adenosine Triphosphate
  • Protein Kinases