Structural insights into FGFR kinase isoform selectivity: diverse binding modes of AZD4547 and ponatinib in complex
Julie A Tucker1, Tobias Klein1, Jason Breed1
1Discovery Sciences, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.
Abstract:
The fibroblast growth factor receptor (FGFR) family of receptor tyrosine kinases has been implicated in a wide variety of cancers. Despite a high level of sequence homology in the ATP-binding site, the majority of reported inhibitors are selective for the FGFR1-3 isoforms and display much reduced potency toward FGFR4, an exception being the Bcr-Abl inhibitor ponatinib. Here we present the crystal structure of the FGFR4 kinase domain and show that both FGFR1 and FGFR4 kinase domains in complex with ponatinib adopt a DFG-out activation loop conformation. Comparison with the structure of FGFR1 in complex with the candidate drug AZD4547, combined with kinetic characterization of the binding of ponatinib and AZD4547 to FGFR1 and FGFR4, sheds light on the observed differences in selectivity profiles and provides a rationale for developing FGFR4-selective inhibitors.
Insights
Fibroblast growth factor receptor 4 (FGFR4) inhibitors are challenging to develop. This study reveals the FGFR4 kinase structure, explaining selectivity differences and guiding the creation of FGFR4-specific cancer drugs.
Area of Science:
- Molecular Biology
- Structural Biology
- Cancer Research
Background:
- The fibroblast growth factor receptor (FGFR) family, including FGFR4, is crucial in various cancers.
- Most FGFR inhibitors target FGFR1-3, with limited potency against FGFR4 due to high sequence homology in the ATP-binding site.
- Ponatinib is an exception, showing activity against FGFR4.
Purpose of the Study:
- To elucidate the structural basis for FGFR4 inhibition selectivity.
- To provide a rationale for developing novel FGFR4-selective inhibitors for cancer therapy.
Main Methods:
- Determined the crystal structure of the FGFR4 kinase domain.
- Analyzed the complex structures of FGFR1 and FGFR4 with ponatinib.
- Performed kinetic characterization of ponatinib and AZD4547 binding to FGFR1 and FGFR4.
Main Results:
- The crystal structure of the FGFR4 kinase domain was determined.
- Both FGFR1 and FGFR4 kinase domains adopt a DFG-out conformation when bound to ponatinib.
- Structural and kinetic data explain the differential selectivity of ponatinib and AZD4547 for FGFR1 and FGFR4.
Conclusions:
- The DFG-out conformation is key to ponatinib's activity against FGFR4.
- Understanding these structural differences provides a foundation for designing FGFR4-specific inhibitors.
- This research paves the way for developing targeted therapies for cancers driven by FGFR4.
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