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5mg |
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25mg |
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50mg |
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100mg |
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250mg |
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500mg |
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Purity: ≥98%
AZD4547 (AZD-4547; AZD 4547) is a novel and orally bioavailable FGFR (fibroblast growth factor receptor) inhibitor with potential antineoplastic activity. In cell-free assays, it inhibits FGFR1/2/3 with IC50s of 0.2 nM/2.5 nM/1.8 nM. However, its activity against other kinases, including FGFR4, VEGFR2(KDR), IGFR, CDK2, and p38, is minimal or weaker. Significant tumor-suppressive effects of AZD4547 are observed in mice with KMS11 tumors with a TGI of 53%.
Targets |
FGFR1 (IC50 = 0.2 nM); FGFR2 (IC50 = 2.5 nM); FGFR3 (IC50 = 1.8 nM); FGFR4 (IC50 = 165 nM)
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ln Vitro |
Fexagratinib also inhibits recombinant VEGFR2 (KDR) kinase activity with an IC50 of 24 nM. Fexagratinib exhibits a powerful inhibition of autophosphorylation of FGFR1, 2, and 3 tyrosine kinases (IC50 values of 12, 2, and 40 nM, respectively) in KG1a, Sum52-PE, MCF7, and KMS11 cell lines. However, it lessens the inhibition of FGFR4 cellular kinase activity (IC50=142 nM). Compared to cellular KDR and IGFR ligand-induced phosphorylation, significantly lower inhibitory activity is seen (IC50 values of 258 and 828 nM, respectively), indicating selectivity over cellular FGFR1 of about 20 and 70 times, respectively. Furthermore, FGFR phosphorylation and downstream signaling mediated by FRS2, PLCγ, and MAPK are potently inhibited by fexagratinib at the cellular level[1].
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ln Vivo |
Fexagratinib is administered chronically at various well-tolerated doses to female SCID mice with KMS11 tumors. The mice are treated in a randomized manner. Tumor growth inhibition is dose-dependent when administered orally with Fexagratinib. When compared to vehicle-treated controls, the administration of Fexagratinib at a dose of 3 mg/kg twice a day results in a statistically significant tumor growth inhibition of 53% (P0.0005 by one-tailed t test), whereas doses of 12.5 mg/kg once daily and 6.25 mg/kg twice a day result in complete tumor stasis (P0.0001). Fexagratinib at a dose of 12.5 mg/kg once daily in the KG1a model was found to be 65% effective in inhibiting tumor growth (P=0.002)[1].
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Enzyme Assay |
AZD4547 is tested with ATP concentrations at or slightly below the corresponding Km to see if it can inhibit the human recombinant kinase activities of FGFR1-3).
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Cell Assay |
For 72 hours, cell lines are incubated with AZD4547 at fixed concentrations. Cells are fixed with 70% ethanol and then incubated with a propidium iodide/RNase A labeling solution for fluorescence-activated cell sorting (FACS). CellQuest analysis software and an FACSCalibur instrument are used to evaluate cell-cycle profiles. Cells and media are carefully collected, centrifuged, and cell pellets are then washed in preparation for apoptotic analysis. Following that, the cells are prepared for propidium iodide uptake and FITC staining. A FACSCalibur device is then used to determine the percentage of cells that stain positively for Annexin V, and CellQuest analysis software is used to sort the cells into quadrants[1].
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Animal Protocol |
Mice: The mice used are Swiss-derived nude (nu/nu) and severe combined immunodeficient (SCID). Tumor xenografts are created by injecting 0.1 mL (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) of tumor cells mixed 1:1 with Matrigel into the left flank, with the exception of LoVo and HCT-15, which do not include Matrigel. Tumors that are larger than 0.2 cm3 are randomly assigned to treatment and control groups, and mice are given AZD4547 (1.5-50 mg/kg) orally once or twice a day. For the duration of the study, tumor condition, animal body weight, and tumor volume (measured using a caliper) are recorded twice a week. One computes the tumor volume.
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References |
Molecular Formula |
C26H33N5O3
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Molecular Weight |
463.57
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Exact Mass |
463.26
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Elemental Analysis |
C, 67.36; H, 7.18; N, 15.11; O, 10.35
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CAS # |
1035270-39-3
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Appearance |
white solid powder
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SMILES |
C[C@@H]1CN(C[C@@H](N1)C)C2=CC=C(C=C2)C(=O)NC3=NNC(=C3)CCC4=CC(=CC(=C4)OC)OC
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InChi Key |
VRQMAABPASPXMW-HDICACEKSA-N
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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+
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Chemical Name |
N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-[(3S,5R)-3,5-dimethylpiperazin-1-yl]benzamide
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Synonyms |
fexagratinib; AZD-4547; AZD 4547; AZD4547
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HS Tariff Code |
2934.99.9001
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Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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Solubility (In Vitro) |
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Solubility (In Vivo) |
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Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
1 mM | 2.1572 mL | 10.7859 mL | 21.5717 mL | |
5 mM | 0.4314 mL | 2.1572 mL | 4.3143 mL | |
10 mM | 0.2157 mL | 1.0786 mL | 2.1572 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration: mg/mL;
Method for preparing DMSO stock solution: mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation::Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O,mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
NCT02299999 | Active Recruiting |
Drug: AZD2014 Drug: AZD4547 |
Metastatic Breast Cancer | UNICANCER | April 7, 2014 | Phase 2 |
NCT02664935 | Active Recruiting |
Drug: AZD4547 Drug: Vistusertib |
Carcinoma, Squamous Cell Adenocarcinoma |
University of Birmingham | May 2015 | Phase 2 |
NCT02546661 | Active Recruiting |
Drug: AZD4547 Drug: MEDI4736 |
Muscle Invasive Bladder Cancer | AstraZeneca | October 3, 2016 | Phase 1 |
NCT05775874 | Recruiting | Drug: AZD4547 Drug: Tislelizumab |
Urothelial Carcinoma | Abbisko Therapeutics Co, Ltd | September 30, 2022 | Phase 2 |
NCT05086666 | Recruiting | Drug: AZD4547 | Urothelial Carcinoma | Abbisko Therapeutics Co, Ltd | June 3, 2021 | Phase 1 Phase 2 |
td> |
AZD4547 exposure correlates with in vivo antitumor activity, pharmacodynamic modulation of phospho-FGFR, and reduced tumor cell proliferation. Cancer Res. 2012 Apr 15;72(8):2045-56. td> |