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AZD4547
本产品不向个人销售,仅用作科学研究,不用于任何人体实验及非科研性质的动物实验。
AZD4547图片
CAS NO:1035270-39-3
规格:≥98%
包装与价格:
包装价格(元)
25mg电议
50mg电议
100mg电议
250mg电议
500mg电议
1g电议

产品介绍
理化性质和储存条件
Molecular Weight (MW)463.57
FormulaC26H33N5O3
CAS No.1035270-39-3
Storage-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)DMSO: 92 mg/mL (198.5 mM)
Water: <1 mg/mL
Ethanol:<1 mg/mL
Solubility (In vivo)4% DMSO+30% PEG 300+5% Tween 80+ddH2O: 5mg/mL
SynonymsAZD-4547; AZD 4547; AZD4547; N-(5-(3,5-dimethoxyphenethyl)-1H-pyrazol-3-yl)-4-((3S,5R)-3,5-dimethylpiperazin-1-yl)benzamide

InChi Key: VRQMAABPASPXMW-HDICACEKSA-N

InChi Code: InChI=1S/C26H33N5O3/c1-17-15-31(16-18(2)27-17)22-9-6-20(7-10-22)26(32)28-25-13-21(29-30-25)8-5-19-11-23(33-3)14-24(12-19)34-4/h6-7,9-14,17-18,27H,5,8,15-16H2,1-4H3,(H2,28,29,30,32)/t17-,18+

SMILES Code: O=C(NC1=NNC(CCC2=CC(OC)=CC(OC)=C2)=C1)C3=CC=C(N4C[C@H](C)N[C@H](C)C4)C=C3

实验参考方法
In Vitro

In vitro activity: Compared to FGFR1-3, AZD4547 displays weaker activity against FGFR4 with IC50 of 165 nM. AZD4547 only inhibits recombinant VEGFR2 (KDR) kinase activity with IC50 of 24 nM, in the in vitro selectivity test against a diverse panel of representative human kinases. AZD4547 at 0.1 μM exhibits no activity against a range of recombinant kinases including ALK, CHK1, EGFR, MAPK1, MEK1, p70S6K, PDGFR, PKB, Src, Tie2, and PI3-kinase. Consistently, the potent selectivity of AZD4547 for FGFR1-3 over FGFR4, IGFR, and KDR is also observed in cellular phosphorylation assays. AZD4547 has potent in vitro antiproliferative activity only against tumor cell lines expressing deregulated FGFRs such as KG1a, Sum52-PE, and KMS11 with IC50 of 18-281 nM, and is inactive against MCF7 as well as more than 100 additional tumor cell lines. AZD4547 treatment potently inhibits FGFR and MAPK phosphorylation in human tumor cell lines in a dose-dependent manner. AZD4547 also potently inhibits the phosphorylation of FRS2 and PLCγ, downstream markers of FGFR signaling. Notably, AZD4547 affects the AKT phosphorylation in the breast cell lines, MCF7 and Sum52-PE but not in KG1a and KMS11 lines. AZD4547 treatment significantly induces apoptosis in Sum52-PE and KMS11 cells, dramatically increases G1 arrest but not apoptosis in KG1a cells, and has no effect on cell cycle distribution or apoptosis in MCF7 cells.


Kinase Assay: The ability of AZD4547 to inhibit the human recombinant kinase activities of FGFR1-3 is tested using ATP concentrations at, or just below, the respective Km.


Cell Assay: Cells (KG1a, Sum52-PE, KMS11, and MCF7) are exposed to various concentrations of AZD4547 for 72 hours. The antiproliferative IC50 values are obtained by MTS proliferation assay. 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.

In VivoOral administration of AZD4547 at 3 mg/kg twice daily in mice bearing KMS11 tumors results in significant tumor growth inhibition of 53% when compared with vehicle-treated controls, and AZD4547 at 12.5 mg/kg once daily or 6.25 mg/kg twice daily leads to complete tumor stasis, which is associated with dose proportional pharmacodynamic modulation of phospho-FGFR3 and reduced KMS11 tumor cell proliferation. Moreover, oral administration of AZD4547 at 12.5 mg/kg once daily results in 65% tumor growth inhibition in the FGFR1-fusion KG1a xenograft model. At efficacious dose levels, AZD4547 does not exhibit antiangiogenic effects. AZD4547 has no significant effect on blood pressure and therefore lacks in vivo anti-KDR activity. Consistently, dosing of 6.25 mg/kg orally twice daily AZD4547 is inactive in the cediranib-sensitive xenograft models including Calu-6, HCT-15 and LoVo.
Animal modelFemale swiss derived nude (nu/nu) and severe combined immunodeficient mice (SCID) bearing LoVo, HCT-15, Calu-6, KMS11 or KG1a tumors
Formulation & DosageFormulated in a 1% (v/v) solution of polyoxyethylenesorbitan monooleate (Tween-80) in deionized water; 1.5-50 mg/kg; oral gavage
References

Cancer Res. 2012 Apr 15;72(8):2045-56.