AZD4547

Modify Date: 2024-01-02 10:52:31

AZD4547 Structure
AZD4547 structure
Common Name AZD4547
CAS Number 1035270-39-3 Molecular Weight 463.572
Density 1.2±0.1 g/cm3 Boiling Point 621.7±55.0 °C at 760 mmHg
Molecular Formula C26H33N5O3 Melting Point N/A
MSDS N/A Flash Point 329.8±31.5 °C

 Use of AZD4547


AZD4547 is a potent inhibitor of the FGFR family with IC50s of 0.2 nM, 2.5 nM, 1.8 nM, and 165 nM for FGFR1, FGFR2, FGFR3, and FGFR4, respectively.

 Names

Name N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-[(3R,5S)-3,5-dimethylpiperazin-1-yl]benzamide
Synonym More Synonyms

 AZD4547 Biological Activity

Description AZD4547 is a potent inhibitor of the FGFR family with IC50s of 0.2 nM, 2.5 nM, 1.8 nM, and 165 nM for FGFR1, FGFR2, FGFR3, and FGFR4, respectively.
Related Catalog
Target

FGFR1:0.2 nM (IC50)

FGFR2:2.5 nM (IC50)

FGFR3:1.8 nM (IC50)

FGFR4:165 nM (IC50)

In Vitro AZD4547 also inhibits recombinant VEGFR2 (KDR) kinase activity with an IC50 of 24 nM. In KG1a, Sum52-PE, MCF7, and KMS11 cell lines, AZD4547 potently inhibits autophosphorylation of FGFR1, 2, and 3 tyrosine kinases (IC50 values of 12, 2, and 40 nM, respectively) and displays weaker inhibition of FGFR4 cellular kinase activity (IC50=142 nM). Significantly weaker inhibitory activity is observed versus cellular KDR and IGFR ligand-induced phosphorylation (IC50 values of 258 and 828 nM, respectively), representing approximately 20- and 70-fold selectivity over cellular FGFR1. Besides, AZD4547 potently inhibits FGFR phosphorylation and downstream signaling affected through FRS2, PLCγ, and MAPK at the cellular level[1].
In Vivo Female SCID mice bearing KMS11 tumors are randomized and treated chronically with AZD4547 at a range of well-tolerated doses. Oral AZD4547 treatment results in dose-dependent tumor growth inhibition. Twice daily administration of AZD4547 at 3 mg/kg gives statistically significant tumor growth inhibition of 53% (P<0.0005 by one-tailed t test) when compare with vehicle-treated controls, whereas doses of 12.5 mg/kg once daily and 6.25 mg/kg twice daily results in complete tumor stasis (P<0.0001). A further efficacy study in the KG1a model with 12.5 mg/kg once daily AZD4547 results in 65% tumor growth inhibition (P=0.002)[1].
Kinase Assay Cells are treated with AZD4547 or control for 3 hours at 37°C and then stimulated with 10 ng/mL aFGF/bFGF and 10 μg/mL heparin for 20 minutes. Western blotting is conducted with standard SDS-PAGE procedures and antibody incubation carried out overnight at 4°C. Antibodies are obtained from the following sources: FGFR1, FGFR2 and FRS2, FGFR3 proteins, α-tubulin-B512 and Bcl2 (C2), and BIM[1].
Cell Assay Cell lines are incubated with fixed concentrations of AZD4547 for 72 hours. For fluorescence-activated cell sorting (FACS), cells are fixed with 70% ethanol and then incubated with propidium iodide/RNase A labeling solution. Cell-cycle profiles are assessed with a FACSCalibur instrument and CellQuest analysis software. For apoptotic analysis, cells and media are gently harvested and centrifuged, followed by washing of cell pellets. Cells are then processed for Annexin V-fluorescein isothiocyanate (FITC) staining and propidium iodide uptake. The proportion of cells staining positive for Annexin V are then assessed with a FACSCalibur instrument and quadrant sorting is done by CellQuest analysis software[1].
Animal Admin Mice[1] Swiss derived nude (nu/nu) and severe combined immunodeficient mice (SCID) are used. Tumor xenografts are established by s.c. injection into the left flank with 0.1 mL tumor cells (1×106 for LoVo, 1×107 for HCT-15, and 1×107 for Calu-6) or 0.2 mL (2×107 for KMS11 and KG1a) mixed 1:1 with Matrigel, with the exception of LoVo and HCT-15, which do not include Matrigel. Mice are randomized into control and treatment groups (AZD4547, 1.5-50 mg/kg, once daily or twice daily by oral gavage) when tumors reach the determined size of more than 0.2 cm3. Tumor volume (measured by caliper), animal body weight, and tumor condition are recorded twice weekly for the duration of the study. Tumor volume is calculated.
References

[1]. Gavine PR, et al. AZD4547: an orally bioavailable, potent, and selective inhibitor of the fibroblast growth factor receptor tyrosine kinase family. Cancer Res, 2012, 72(8), 2045-2056.

 Chemical & Physical Properties

Density 1.2±0.1 g/cm3
Boiling Point 621.7±55.0 °C at 760 mmHg
Molecular Formula C26H33N5O3
Molecular Weight 463.572
Flash Point 329.8±31.5 °C
Exact Mass 463.258331
PSA 95.00000
LogP 3.46
Vapour Pressure 0.0±1.8 mmHg at 25°C
Index of Refraction 1.602

 Safety Information

Hazard Codes Xi

 Synonyms

AZD4547
azd 4547
qcr-89
Benzamide, N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-[(3R,5S)-3,5-dimethyl-1-piperazinyl]-
N-{5-[2-(3,5-Dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl}-4-[(3R,5S)-3,5-dimethyl-1-piperazinyl]benzamide
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