Small molecule recognition of c-Src via the Imatinib-binding conformation

Chem Biol. 2008 Oct 20;15(10):1015-22. doi: 10.1016/j.chembiol.2008.09.007.


The cancer drug, Imatinib, is a selective Abl kinase inhibitor that does not inhibit the closely related kinase c-Src. This one drug and its ability to selectively inhibit Abl over c-Src has been a guiding principle in virtually all kinase drug discovery efforts in the last 15 years. A prominent hypothesis explaining the selectivity of Imatinib is that Abl has an intrinsic ability to adopt an inactive conformation (termed DFG-out), whereas c-Src appears to pay a high intrinsic energetic penalty for adopting this conformation, effectively excluding Imatinib from its ATP pocket. This explanation of the difference in binding affinity of Imatinib for Abl versus c-Src makes the striking prediction that it would not be possible to design an inhibitor that binds to the DFG-out conformation of c-Src with high affinity. We report the discovery of a series of such inhibitors. We use structure-activity relationships and X-ray crystallography to confirm our findings. These studies suggest that small molecules are capable of inducing the generally unfavorable DFG-out conformation in c-Src. Structural comparison between c-Src in complex with these inhibitors allows us to speculate on the differential selectivity of Imatinib for c-Src and Abl.

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

  • Benzamides
  • Crystallography, X-Ray
  • Imatinib Mesylate
  • Models, Molecular
  • Molecular Structure
  • Pharmaceutical Preparations / chemistry*
  • Piperazines / chemistry*
  • Protein Binding
  • Proto-Oncogene Proteins pp60(c-src) / chemistry
  • Proto-Oncogene Proteins pp60(c-src) / genetics
  • Proto-Oncogene Proteins pp60(c-src) / metabolism*
  • Pyrimidines / chemistry*


  • Benzamides
  • Pharmaceutical Preparations
  • Piperazines
  • Pyrimidines
  • Imatinib Mesylate
  • Proto-Oncogene Proteins pp60(c-src)

Associated data

  • PDB/3EL7
  • PDB/3EL8