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Updated: Jun 28, 2026
A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
Published on: December 7, 2014
Small molecule recognition of c-Src via the Imatinib-binding conformation
Arvin C Dar1, Michael S Lopez, Kevan M Shokat
1Department 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.
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.
Insights
Researchers discovered new inhibitors that bind to the inactive DFG-out conformation of c-Src, challenging previous hypotheses about kinase selectivity and drug design for cancer therapies.
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Structural Biology
Background:
- Imatinib is a selective Abl kinase inhibitor, not inhibiting the related c-Src kinase.
- This selectivity has guided kinase drug discovery for 15 years.
- A hypothesis suggests Abl adopts an inactive DFG-out conformation, unlike c-Src, explaining Imatinib's binding.
Purpose of the Study:
- To challenge the hypothesis that c-Src cannot bind inhibitors in its DFG-out conformation.
- To discover novel inhibitors targeting the c-Src DFG-out state.
- To understand the structural basis for differential kinase selectivity.
Main Methods:
- Structure-activity relationship studies.
- X-ray crystallography.
- Biochemical assays to assess kinase inhibition.
Main Results:
- Discovery of novel small molecule inhibitors targeting c-Src.
- Confirmation that these inhibitors bind to the c-Src DFG-out conformation.
- Structural data revealing how inhibitors induce this conformation in c-Src.
Conclusions:
- Small molecules can induce the unfavorable DFG-out conformation in c-Src.
- This finding refutes the previous hypothesis regarding c-Src's inability to adopt this state.
- Provides new insights into designing selective kinase inhibitors, potentially impacting cancer drug discovery.
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