4WUN

Structure of FGFR1 in complex with AZD4547 (N-{3-[2-(3,5-DIMETHOXYPHENYL)ETHYL]-1H-PYRAZOL-5-YL}-4-[(3R,5S)-3,5-DIMETHYLPIPERAZIN-1-YL]BENZAMIDE) at 1.65 angstrom

Summary for 4WUN

• Entry DOI: 10.2210/pdb4wun/pdb
• Descriptor: Fibroblast growth factor receptor 1, N-{3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-5-yl}-4-[(3R,5S)-3,5-dimethylpiperazin-1-yl]benzamide (3 entities in total)
• Functional Keywords: transferase; transferase inhibitor complex, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cell membrane; Single-pass type I membrane protein: P11362
• Total number of polymer chains: 2
• Total formula weight: 71634.37

Authors

Squire, C.J.,Yosaatmadja, C.J. (deposition date: 2014-11-02, release date: 2014-11-19, Last modification date: 2023-09-27)

Primary citation

Yosaatmadja, Y.,Patterson, A.V.,Smaill, J.B.,Squire, C.J.
The 1.65 angstrom resolution structure of the complex of AZD4547 with the kinase domain of FGFR1 displays exquisite molecular recognition.
Acta Crystallogr.,Sect.D, 71:525-533, 2015

PubMed 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.

PubMed: 25760602
DOI: 10.1107/S1399004714027539

Experimental method

X-RAY DIFFRACTION (1.65 Å)