title: Structural insights into FGFR kinase isoform selectivity: diverse binding modes of AZD4547 and ponatinib in complex with FGFR1 and FGFR4.
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.
authors.affiliation: Discovery Sciences, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Tucker
authors.affiliation: Discovery Sciences, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.
authors.forename: Tobias
authors.initials: T
authors.lastname: Klein
authors.affiliation: Discovery Sciences, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.
authors.forename: Jason
authors.initials: J
authors.lastname: Breed
authors.affiliation: Discovery Sciences, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Breeze
authors.affiliation: Discovery Sciences, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.
authors.forename: Ross
authors.initials: R
authors.lastname: Overman
authors.affiliation: Discovery Sciences, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Phillips
authors.affiliation: Discovery Sciences, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK. Electronic address: richard.norman@astrazeneca.com.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Norman
mesh_terms: D001549:Benzamides / Q000494:pharmacology*; D002460:Cell Line; D004926:Escherichia coli; D007093:Imidazoles / Q000494:pharmacology*; D008024:Ligands; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D011485:Protein Binding; D020033:Protein Isoforms / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology*; D011724:Pyridazines / Q000494:pharmacology*; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism*; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C572463:AZD4547; D001549:Benzamides; D007093:Imidazoles; D008024:Ligands; D010879:Piperazines; D020033:Protein Isoforms; D011720:Pyrazoles; D011724:Pyridazines; C545373:ponatinib; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051499:Receptor, Fibroblast Growth Factor, Type 4