Energetic Dissection of Gleevec's Selectivity Toward Human Tyrosine Kinases

Nat Struct Mol Biol. 2014 Oct;21(10):848-53. doi: 10.1038/nsmb.2891. Epub 2014 Sep 14.


Protein kinases are obvious drug targets against cancer, owing to their central role in cellular regulation. Since the discovery of Gleevec, a potent and specific inhibitor of Abl kinase, as a highly successful cancer therapeutic, the ability of this drug to distinguish between Abl and other tyrosine kinases such as Src has been intensely investigated but without much success. Using NMR and fast kinetics, we establish a new model that solves this longstanding question of how the two tyrosine kinases adopt almost identical structures when bound to Gleevec but have vastly different affinities. We show that, in contrast to all other proposed models, the origin of Abl's high affinity lies predominantly in a conformational change after binding. An energy landscape providing tight affinity via an induced fit and binding plasticity via a conformational-selection mechanism is likely to be general for many inhibitors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Benzamides / chemistry
  • Benzamides / pharmacology*
  • Cell Line
  • Humans
  • Imatinib Mesylate
  • Kinetics
  • Neoplasms / enzymology*
  • Piperazines / chemistry
  • Piperazines / pharmacology*
  • Protein Binding
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins c-abl / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-abl / chemistry*
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Thermodynamics*
  • src-Family Kinases / ultrastructure


  • Antineoplastic Agents
  • Benzamides
  • Piperazines
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Imatinib Mesylate
  • Proto-Oncogene Proteins c-abl
  • src-Family Kinases