AZD4547

Catalog No.S2801 Batch:S280102

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Technical Data

Formula

C26H33N5O3
Molecular Weight 463.57 CAS No. 1035270-39-3
Solubility (25°C)* In vitro DMSO 93 mg/mL (200.61 mM)
Ethanol 40 mg/mL (86.28 mM)
Water Insoluble
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
* Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.)

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Biological Activity

Description AZD4547 (ABSK 091) is a novel selective FGFR inhibitor targeting FGFR1/2/3 with IC50 of 0.2 nM/2.5 nM/1.8 nM in cell-free assays, weaker activity against FGFR4, VEGFR2(KDR), and little activity observed against IGFR, CDK2, and p38. Phase 2/3.
Targets
FGFR1 [1]
(Cell-free assay)		 FGFR3 [1]
(Cell-free assay)		 FGFR2 [1]
(Cell-free assay)		 KDR [1]
(Cell-free assay)
0.2 nM 1.8 nM 2.5 nM 24 nM
In vitro 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. [1]
In vivo Oral 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. [1]
Features Greater selectivity for FGFR1-3 over FGFR4. AZD4547 is active against the tyrosine kinase activity of both the wild-type and mutant forms of FGFR.

Protocol (from reference)

Kinase Assay:[1]
  • AZD4547 kinase activity

    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:[1]
  • Cell lines

    KG1a, Sum52-PE, KMS11, and MCF7

  • Concentrations

    Dissolved in DMSO, final concentrations ~1 μM

  • Incubation Time

    72 hours

  • Method

    Cells 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.
Animal Study:[1]
  • Animal Models

    Female swiss derived nude (nu/nu) and severe combined immunodeficient mice (SCID) injected s.c. with LoVo, HCT-15, Calu-6, KMS11 or KG1a

  • Dosages

    1.5-50 mg/kg

  • Administration

    Oral gavage once daily or twice daily

Customer Product Validation

Data from [Cell Physiol Biochem, 2014, 33(3), 633-45]

Data from [Data independently produced by Mol Cell Biol, 2014, 34(18), 3535-45]

, , Science, 2017, doi: 10.1126/science.aan4368

, , Oncogene, 2017, 36(27):3831-3841

Selleck's AZD4547 has been cited by 135 publications

FKBP10 promotes clear cell renal cell carcinoma progression and regulates sensitivity to the HIF2α blockade by facilitating LDHA phosphorylation [ Cell Death Dis, 2024, 15(1):64] PubMed: 38233415
Paradoxical cancer cell proliferation after FGFR inhibition through decreased p21 signaling in FGFR1-amplified breast cancer cells [ Breast Cancer Res, 2024, 26(1):54] PubMed: 38553760
Hyperglycemia activates FGFR1 via TLR4/c-Src pathway to induce inflammatory cardiomyopathy in diabetes [ Acta Pharmaceutica Sinica B, 2024, 10.1016/j.apsb.2024.01.013] PubMed: none
The Combination of Afatinib With Dasatinib or Miransertib Results in Synergistic Growth Inhibition of Stomach Cancer Cells [ World J Oncol, 2024, 15(2):192-208] PubMed: 38545471
Resistance to Selective FGFR Inhibitors in FGFR-Driven Urothelial Cancer [ Cancer Discov, 2023, 13(9):1998-2011] PubMed: 37377403
Resistance to Selective FGFR Inhibitors in FGFR-Driven Urothelial Cancer [ Cancer Discov, 2023, 13(9):1998-2011] PubMed: 37377403
Resistance to Selective FGFR Inhibitors in FGFR-Driven Urothelial Cancer [ Cancer Discov, 2023, 13(9):1998-2011] PubMed: 37377403
Kinome Reprogramming Is a Targetable Vulnerability in ESR1 Fusion-Driven Breast Cancer [ Cancer Res, 2023, 83(19):3237-3251] PubMed: 37071495
A GSTP1-mediated lactic acid signaling promotes tumorigenesis through the PPP oxidative branch [ Cell Death Dis, 2023, 14(7):463] PubMed: 37491277
A GSTP1-mediated lactic acid signaling promotes tumorigenesis through the PPP oxidative branch [ Cell Death Dis, 2023, 14(7):463] PubMed: 37491277

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SHIPPING AND STORAGE
Selleck products are transported at room temperature. If you receive the product at room temperature, please rest assured, the Selleck Quality Inspection Department has conducted experiments to verify that the normal temperature placement of one month will not affect the biological activity of powder products. After collecting, please store the product according to the requirements described in the datasheet. Most Selleck products are stable under the recommended conditions.

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