Structural approaches to obtain kinase selectivity

Trends Pharmacol Sci. 2012 May;33(5):273-8. doi: 10.1016/ Epub 2012 Apr 11.


One of the grand challenges in kinase drug discovery is the design of small-molecule inhibitors with selectivity profiles that will ultimately be efficacious in the clinic. Current medicinal chemistry strategies make heavy use of structural, biophysical and computational approaches to achieve this multi-faceted goal. Here we review structure-based approaches underlying the development of several molecules that are currently in clinical trials, including the cMet inhibitor ARQ197 and the Bcr-Abl inhibitor ponatinib. We highlight the challenge posed by the emergence of resistance mutants and discuss promising lead generation strategies to obtain selective inhibitors of protein and lipid kinases such as targeting of specific sites, the use of fragment-based approaches and new chemical probes based on metal complexes.

Publication types

  • Review

MeSH terms

  • Adenosine Triphosphate / chemistry
  • Binding Sites
  • Drug Design
  • Humans
  • Protein Binding
  • Protein Conformation
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinases / chemistry*
  • Protein Kinases / metabolism


  • Protein Kinase Inhibitors
  • Adenosine Triphosphate
  • Protein Kinases