title: The 1.65 Å resolution structure of the complex of AZD4547 with the kinase domain of FGFR1 displays exquisite molecular recognition.
abstract: The fibroblast growth factor receptor (FGFR) family are expressed widely in normal tissues and play a role in tissue repair, inflammation, angiogenesis and development. However, aberrant signalling through this family can lead to cellular proliferation, evasion of apoptosis and induction of angiogenesis, which is implicated in the development of many cancers and also in drug resistance. The high frequency of FGFR amplification or mutation in multiple cancer types is such that this family has been targeted for the discovery of novel, selective drug compounds, with one of the most recently discovered being AZD4547, a subnanomolar (IC50) FGFR1 inhibitor developed by AstraZeneca and currently in clinical trials. The 1.65 Å resolution crystal structure of AZD4547 bound to the kinase domain of FGFR1 has been determined and reveals extensive drug-protein interactions, an integral network of water molecules and the tight closure of the FGFR1 P-loop to form a long, narrow crevice in which the AZD4547 molecule binds.
authors.affiliation: School of Biological Sciences, The University of Auckland, Private Bag 92019, Auckland, New Zealand.
authors.forename: Yuliana
authors.initials: Y
authors.lastname: Yosaatmadja
authors.affiliation: Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland, New Zealand.
authors.forename: Adam Vorn
authors.initials: AV
authors.lastname: Patterson
authors.affiliation: Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland, New Zealand.
authors.forename: Jeff Bruce
authors.initials: JB
authors.lastname: Smaill
authors.affiliation: School of Biological Sciences, The University of Auckland, Private Bag 92019, Auckland, New Zealand.
authors.forename: Christopher John
authors.initials: CJ
authors.lastname: Squire
mesh_terms: D001549:Benzamides / Q000737:chemistry*; D018360:Crystallography, X-Ray; D006801:Humans; D010879:Piperazines / Q000737:chemistry*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011720:Pyrazoles / Q000737:chemistry*; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000737:chemistry* / Q000235:genetics
chemical_list: C572463:AZD4547; D001549:Benzamides; D010879:Piperazines; D011720:Pyrazoles; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1
keywords: AZD4547; fibroblast growth factor receptor