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Structural Insights into FGFR Kinase Isoform Selectivity: Diverse Binding Modes of AZD4547 and Ponatinib in Complex with FGFR1 and FGFR4

Lookup NU author(s): Dr Julie Tucker

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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.

Publication metadata

Author(s): Tucker JA, Klein T, Breed J, Breeze AL, Overman R, Phillips C, Norman RA

Publication type: Article

Publication status: Published

Journal: Structure

Year: 2014

Volume: 22

Issue: 12

Pages: 1764-1774

Print publication date: 02/12/2014

Online publication date: 20/11/2014

Acceptance date: 24/09/2014

ISSN (print): 0969-2126

ISSN (electronic): 1878-4186

Publisher: Cell Press

URL: http://dx.doi.org/10.1016/j.str.2014.09.019

DOI: 10.1016/j.str.2014.09.019

PubMed id: 25465127

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