The 1.65 Å resolution structure of the complex of AZD4547 with the kinase domain of FGFR1 displays exquisite molecular recognition

Acta Crystallographica. Section D, Biological Crystallography
Yuliana YosaatmadjaChristopher John Squire

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.

References

Feb 17, 1999·Frontiers in Bioscience : a Journal and Virtual Library·P Klint, L Claesson-Welsh
May 3, 2005·Cytokine & Growth Factor Reviews·Moosa MohammadiOmar A Ibrahimi
May 3, 2005·Cytokine & Growth Factor Reviews·V P EswarakumarJ Schlessinger
Apr 7, 2006·The Journal of Biological Chemistry·Xiuqin ZhangDavid M Ornitz
Nov 11, 2006·Proceedings of the National Academy of Sciences of the United States of America·Alexandr P KornevLynn F Ten Eyck
Feb 22, 2008·Proceedings of the National Academy of Sciences of the United States of America·James TsaiGideon Bollag
Oct 23, 2008·Chemistry & Biology·Arvin C DarKevan M Shokat
Feb 28, 2009·Nature Reviews. Drug Discovery·Andrew Beenken, Moosa Mohammadi
Aug 1, 2007·Journal of Applied Crystallography·Airlie J McCoyRandy J Read
Jan 9, 2010·Acta Crystallographica. Section D, Biological Crystallography·Vincent B ChenDavid C Richardson
Jan 23, 2010·Nature Reviews. Cancer·Nicholas Turner, Richard Grose
Feb 4, 2010·Acta Crystallographica. Section D, Biological Crystallography·Wolfgang Kabsch
Mar 27, 2010·Chemistry & Biology·Wenjun ZhouNathanael S Gray
Apr 13, 2010·Acta Crystallographica. Section D, Biological Crystallography·P EmsleyK Cowtan
Jul 1, 2010·Current Medicinal Chemistry·L GarutiG Bottegoni
Apr 5, 2011·Acta Crystallographica. Section D, Biological Crystallography·Garib N MurshudovAlexei A Vagin
May 17, 2011·Journal of Chemical Information and Modeling·Cristiano R W GuimarãesLeonard Buckbinder
Jun 30, 2011·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Rachel SharpeNicholas C Turner
Aug 24, 2011·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Jonathan A LedermannGordon Rustin
Oct 7, 2011·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Kevin B KimJohn M Kirkwood
Oct 7, 2011·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Maria NietoFrancesco Pignatti
Nov 25, 2011·Future Oncology·Bernd Kasper, Peter Hohenberger
Mar 6, 2012·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·A Nigel BrooksPaul D Smith
May 23, 2012·Journal of Medicinal Chemistry·Richard A NormanAndrew G Leach
Jul 4, 2012·Nature Reviews. Clinical Oncology·Isabelle Ray-Coquard, David Thomas
Aug 14, 2012·Trends in Pharmacological Sciences·Guang LiangXiaokun Li
Oct 4, 2012·Future Oncology·Tina Chou, Richard S Finn
Oct 26, 2012·Anti-cancer Agents in Medicinal Chemistry·Javier BlancChristel Menet
Jun 26, 2013·Acta Crystallographica. Section D, Biological Crystallography·Philip R Evans, Garib N Murshudov

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Citations

Nov 3, 2015·Journal of Structural Biology·Yuliana YosaatmadjaChristopher J Squire
Nov 26, 2019·European Journal of Medicinal Chemistry·Feng-Tao LiuZhi-Hao Shi
Mar 10, 2018·Journal of Medicinal Chemistry·Yuming WangWenhu Duan
Aug 16, 2019·ACS Medicinal Chemistry Letters·Xiaojing LinChristopher J Squire

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