3EL8

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

(2008) Chem Biol 15: 1015-1022

• PubMed: 18940662 Search on PubMedSearch on PubMed Central
• DOI: https://doi.org/10.1016/j.chembiol.2008.09.007
• Primary Citation of Related Structures:  
  3EL7, 3EL8


• PubMed Abstract: 
  

  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.

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Organizational Affiliation: 

Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, Genentech Hall, 600 16(th) Street, University of California, San Francisco, San Francisco, CA 94158, USA.