A general framework for inhibitor resistance in protein kinases

Chem Biol. 2011 Aug 26;18(8):966-75. doi: 10.1016/j.chembiol.2011.04.013.


Protein kinases control virtually every aspect of normal and pathological cell physiology and are considered ideal targets for drug discovery. Most kinase inhibitors target the ATP binding site and interact with residue of a hinge loop connecting the small and large lobes of the kinase scaffold. Resistance to kinase inhibitors emerges during clinical treatment or as a result of in vitro selection approaches. Mutations conferring resistance to ATP site inhibitors often affect residues that line the ATP binding site and therefore contribute to selective inhibitor binding. Here, we show that mutations at two specific positions in the hinge loop, distinct from the previously characterized "gatekeeper," have general adverse effects on inhibitor sensitivity in six distantly related kinases, usually without consequences on kinase activity. Our results uncover a unifying mechanism of inhibitor resistance of protein kinases that might have widespread significance for drug target validation and clinical practice.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • CSK Tyrosine-Protein Kinase
  • Drug Resistance*
  • HeLa Cells
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation*
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinases / genetics*
  • Protein Kinases / metabolism
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism
  • Sequence Alignment
  • Tubercidin / analogs & derivatives
  • Tubercidin / pharmacology
  • src-Family Kinases


  • Protein Kinase Inhibitors
  • 5-iodotubercidin
  • Protein Kinases
  • Protein-Tyrosine Kinases
  • CSK Tyrosine-Protein Kinase
  • src-Family Kinases
  • CSK protein, human
  • Tubercidin