AZD4547

Catalog No.S2801

AZD4547 Chemical Structure

Molecular Weight(MW): 463.57

AZD4547 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.

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Cited by 29 Publications

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Biological Activity

Description AZD4547 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.
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.
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]

Cell Data
Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
SNU449 MVfHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M37GWFczKGh? MX;JR|UxRTBwMEiyJO69VQ>? MXiyOlM2OTN{MB?=
SK-HEP-1 M1nl[mdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NYD1ZWZ6PzJiaB?= M1fOSmlEPTB;MD6wPFQh|ryP MVmyOlM2OTN{MB?=
SNU475 NVTRNmhCT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M3rkVlczKGh? NI\iVoxKSzVyPUWuOEDPxE1? M{HG[VI3OzVzM{Kw
Hep3B M2TSbWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NFzucWU4OiCq MkfsTWM2OD14LkSzJO69VQ>? M1nKT|I3OzVzM{Kw
PLC/PRF5 Mo\QS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NHPxXXc4OiCq NIPMZVRKSzVyPU[uOVUh|ryP MYeyOlM2OTN{MB?=
Hur7 MYrHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NGn0RYE4OiCq NITIflNKSzVyPUeuNlUh|ryP MYKyOlM2OTN{MB?=
HepG2 MV7Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NX;xTZdvPzJiaB?= NELwN4hKSzVyPUiuO|Mh|ryP MWiyOlM2OTN{MB?=
SNU449 NUXid5dGS2yxbn;n[Y5q[yCjc4PhfS=> NV7ySIZOOSEEtV2= NVnDT5l4OjRiaB?= NU\xZZFD\GWlcnXhd4V{KGOxbH;ufUBnd3KvYYTpc44he2mpbnnmbYNidnSueR?= NWfjeGd1OjZ|NUGzNlA>
SK-HEP-1 NVi5WoVsS2yxbn;n[Y5q[yCjc4PhfS=> NV7qN4FVOSEEtV2= MlfyNlQhcA>? MkjL[IVkemWjc3XzJINwdG:weTDmc5Ju[XSrb36gd4lodmmoaXPhcpRtgQ>? MXOyOlM2OTN{MB?=
SNU449 NVH1e4FNTnWwY4Tpc44hSXO|YYm= MmPmNE0zKM7:TR?= NX3aPGhSPDhiaB?= NIO0dVZk[XW|ZYOgZUBl\WO{ZXHz[UBw\iCIUmOy89yNSUuWLDDhcoQhTVKNIIDoc5NxcG:{eXzheIlwdg>? MYqyOlM2OTN{MB?=
SK-HEP-1 NGf6OpNHfW6ldHnvckBCe3OjeR?= MknjNE0zKM7:TR?= MmT0OFghcA>? NYXzRpJO[2G3c3XzJIEh\GWlcnXhd4Uhd2ZiRmLTNw+9lEGNVDygZY5lKEWUSzDwbI9{eGixconsZZRqd25? Mlm5NlY{PTF|MkC=
BaF3 FLT3-TEL NGLGTW1Iem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NFTmPFdIUTVyPUSuOkDDuSByLkW3O{DPxE1? MXSyOlI6PDd2MR?=
BaF3 RET-TEL MXrHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? Mki2S2k2OD1yLkO5JOKyKDBwMES4JO69VQ>? MWqyOlI6PDd2MR?=
BaF3 Parental NHjse5JIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NUfuSnoyT0l3MP-5qVExKM7:TR?= NEPlWmszPjJ7NEe0NS=>
MOLM14 FLT3/ITD NWrxWVZRT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MoGyS2k2OD1yLkS4OEDDuSByLkG1O{DPxE1? MVSyOlI6PDd2MR?=
MV4-11 FLT3/ITD MUnHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NF74UYtIUTVyPUCuOFU6KMLzIECuNFQ3KM7:TR?= MkjlNlYzQTR5NEG=
TT RET C634W M{PQXGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M2jtdGdKPTB;Mj65JOKyKDBwOUC0JO69VQ>? Ml\oNlYzQTR5NEG=
AN3-CA FGFR2 N550K, K310R NEX2fW5Iem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NHjWVYFIUTVyPUCuNFMyKMLzIECuNFI{KM7:TR?= NXO2Opp5OjZ{OUS3OFE>
MFE296 FGFR2 N550K NWrTO2pnT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NVvnPYdyT0l3ME2wMlc{OCEEsTCwMlA2PyEQvF2= M1zNdlI3Ojl2N{Sx
MFE280 FGFR2 S252W MV7Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MojJS2k2OD1yLkKxPEDDuSByLkC3N{DPxE1? NY[2VVBoOjZ{OUS3OFE>
Ishikawa FGFF2 over exp. NVXoVXlmT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NIDqO2dIUTVyPUSuOUDDuSBzLkWxJO69VQ>? MVKyOlI6PDd2MR?=
HEC1A Normal FGFR2 NWKzWoI4T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NX3QXoxRT0l3MP-5qVExKM7:TR?= MXeyOlI6PDd2MR?=
A549 NF;L[mtE\WyuII\pZYJqdGm2eTDBd5NigQ>? Ml;INE4yNzFizszN MUi0PEBp MUHlcohidmOnczDFdoxwfGmwaXKgbY5lfWOnZDD2bYFjcWyrdImgcI9{ew>? MWiyOlA2OzB{MB?=
SGC-7901 MWTHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MnTENUBvVS1zMDFOwG0> MlizO|IhcA>? MmrJTWM2OCCxZjC1MVExKM7:TTygbY5pcWKrdIOgZ4VtdCC4aXHibYxqfHliZH;z[UBl\XCnbnTlcpRtgQ>? MV6yOVU4PjlzNR?=
HGC-27 MnS5S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M{Ttc|Ehdk1vMUCg{txO NYG3TFg3PzJiaB?= M4D6TGlEPTBib3[gOU0yOCEQvF2sJIlvcGmkaYTzJINmdGxidnnhZoltcXS7IHTvd4Uh\GWyZX7k[Y51dHl? M1fkcFI2PTd4OUG1
MKN-28 M37jTmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M3y2[FEhdk1vMUCg{txO MX[3NkBp MnraTWM2OCCxZjC1MVExKM7:TTygbY5pcWKrdIOgZ4VtdCC4aXHibYxqfHliZH;z[UBl\XCnbnTlcpRtgQ>? M2XkRVI2PTd4OUG1
NCI-N87 M1zW[2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MVexJI5ONTFyIN88US=> NX:zPYxXPzJiaB?= NX;2W2lDUUN3MDDv[kA2NTFyIN88UUwhcW6qaXLpeJMh[2WubDD2bYFjcWyrdImg[I9{\SCmZYDlcoRmdnSueR?= NVzMU5FjOjV3N{[5NVU>
KATOIII NHXhVVZIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NU[1bJFUOSCwTT2xNEDPxE1? Mn\kO|IhcA>? MkPyTWM2OCCxZjCxNE0yODBibl2sJIlvcGmkaYTzJINmdGxidnnhZoltcXS7IHTvd4Uh\GWyZX7k[Y51dHl? Mn\5NlU2PzZ7MUW=
SNU-16 NEXodYVIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MYGxJI5ONTFyIN88US=> NUHkSo1tPzJiaB?= NVzxTJE{UUN3MDDv[kAyOC1zMECgcm0tKGmwaHnibZR{KGOnbHygeoli[mmuaYT5JIRwe2ViZHXw[Y5l\W62bIm= M3j3SlI2PTd4OUG1
4T1 M1TD[Gdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MkfFTWM2OD1yLk[0xtExNjFzIN88US=> NFrTOmgzPDZ2Mki5Ny=>
MDA-MB-468 MV3Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MmPmTWM2OD12LkpCtVAvQDVizszN NHP2b|AzPDZ2Mki5Ny=>
HCT116 MYjHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NY[2eYg6UUN3ME2xOU46yrFzLkiyJO69VQ>? M1j2b|I1PjR{OEmz
SW620 MX\Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NHXRVnlKSzVy78{eNlAh|ryP M3;uVFI1PjR{OEmz
MDA-MB-231 MYnHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NInxPHNKSzVy78{eNlAh|ryP NXPKeGV3OjR4NEK4PVM>
CT26 MoL0S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NWLEWXdqUUN3MP-8olIxKM7:TR?= MU[yOFY1Ojh7Mx?=
SW480 M1PzbGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M1LXRWlEPTExvK6yNEDPxE1? MUSyOFY1Ojh7Mx?=
4T1 NVqyZYlYSXCxcITvd4l{KEG|c3H5 Mn\INU4zPS1{MDFOwG0> NX3XZWY2OjRiaB?= NUW4[YJNcW6mdXPld{BieG:ydH;zbZMh\G:|ZTDk[ZBmdmSnboTsfS=> M3vxR|I1PjR{OEmz
KG1a MYHHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NHfEdGhKSzVyPUCuNFE5KM7:TR?= NXvQ[XZyOjJ|Nkm5Nlg>
Sum52-PE NWq0[mZrT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M1nsUWlEPTB;MD6wOFEh|ryP NX3TPGVEOjJ|Nkm5Nlg>
KMS11 NU\ZZnNOT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M2fTeGlEPTB;MD6yPFEh|ryP NW\wcIFSOjJ|Nkm5Nlg>
MCF7 NEPSN4VIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M2e5O2lEPTB-M{Cg{txO NGnCdVYzOjN4OUmyPC=>

... Click to View More Cell Line Experimental Data

Assay
Methods Test Index PMID
Western blot
p-FGFR / FGFR1 / p-AKT / AKT / p-ERK / ERK; 

PubMed: 28900173     


Western blots (cropped) are shown for the indicated proteins in MDA-MB-361, BT474, and SKBR3 cells treated with AZD4547 (0, 1, 3, or 5 µM) for 72 hours. 

pFRS2; 

PubMed: 25576915     


AZD4547 inhibits FGFR2 pathway activation in SNU16 and KATOIII cells. Cells were incubated with AZD4547 at the indicated doses. Cell lysates were immunoblotted for phospho-FGFR, phospho-FRS2, phospho- and total AKT, and phospho- and total ERK.

28900173 25576915
Growth inhibition assay
Cell viability; 

PubMed: 28900173     


MDA-MB-361, BT474, and SKBR3 ErbB2-overexpressing breast cancer cells were treated with AZD4547 (0, 0.1, 0.3, 1, 3, or 5 µM) for 5 days. Then the viable fraction of each cell line was determined with an MTS assay. 

Cell viability; 

PubMed: 25576915     


FGFR2-amplified GC cells are selectively sensitive to AZD4547. In vitro CCK-8 assay across a panel of 6 GC cells demonstrated that SNU16 and KATOIII cells were extremely sensitive to AZD4547 with IC50 values of 5-10 nM. Data (n = 6) are presented as mean ± SD.

28900173 25576915
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]

Protocol

Kinase Assay:[1]
+ Expand

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 Research:[1]
+ Expand
  • 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.
    (Only for Reference)
Animal Research:[1]
+ Expand
  • 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
  • Formulation: Formulated in a 1% (v/v) solution of polyoxyethylenesorbitan monooleate (Tween-80) in deionized water
  • Dosages: 1.5-50 mg/kg
  • Administration: Oral gavage once daily or twice daily
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 92 mg/mL (198.45 mM)
Water Insoluble
Ethanol Insoluble
In vivo Add solvents to the product individually and in order(Data is from Selleck tests instead of citations):
4% DMSO+30% PEG 300+5% Tween 80+ddH2O
For best results, use promptly after mixing.
5mg/mL

* 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.

Chemical Information

Molecular Weight 463.57
Formula

C26H33N5O3

CAS No. 1035270-39-3
Storage powder
in solvent
Synonyms N/A

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Clinical Trial Information

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT02546661 Recruiting Muscle Invasive Bladder Cancer AstraZeneca October 3 2016 Phase 1
NCT02546661 Recruiting Muscle Invasive Bladder Cancer AstraZeneca October 3 2016 Phase 1
NCT02824133 Suspended Recurrent IDHwt Gliomas With FGFR3-TACC3 Fusion|Recurrent IDHwt Gliomas With FGFR1-TACC1 Fusion Assistance Publique - Hôpitaux de Paris September 2015 Phase 1|Phase 2
NCT02824133 Suspended Recurrent IDHwt Gliomas With FGFR3-TACC3 Fusion|Recurrent IDHwt Gliomas With FGFR1-TACC1 Fusion Assistance Publique - Hôpitaux de Paris September 2015 Phase 1|Phase 2
NCT02465060 Recruiting Advanced Malignant Solid Neoplasm|Bladder Carcinoma|Breast Carcinoma|Cervical Carcinoma|Colon Carcinoma|Colorectal Carcinoma|Endometrial Carcinoma|Esophageal Carcinoma|Gastric Carcinoma|Glioma|Head and Neck Carcinoma|Kidney Carcinoma|Liver and Intrahepatic Bile Duct Carcinoma|Lung Carcinoma|Lymphoma|Malignant Uterine Neoplasm|Melanoma|Ovarian Carcinoma|Pancreatic Carcinoma|Plasma Cell Myeloma|Prostate Carcinoma|Rectal Carcinoma|Recurrent Bladder Carcinoma|Recurrent Breast Carcinoma|Recurrent Cervical Carcinoma|Recurrent Colon Carcinoma|Recurrent Colorectal Carcinoma|Recurrent Esophageal Carcinoma|Recurrent Gastric Carcinoma|Recurrent Glioma|Recurrent Head and Neck Carcinoma|Recurrent Liver Carcinoma|Recurrent Lung Carcinoma|Recurrent Lymphoma|Recurrent Malignant Solid Neoplasm|Recurrent Melanoma|Recurrent Ovarian Carcinoma|Recurrent Pancreatic Carcinoma|Recurrent Plasma Cell Myeloma|Recurrent Prostate Carcinoma|Recurrent Rectal Carcinoma|Recurrent Skin Carcinoma|Recurrent Thyroid Gland Carcinoma|Recurrent Uterine Corpus Carcinoma|Refractory Lymphoma|Refractory Malignant Solid Neoplasm|Refractory Plasma Cell Myeloma|Skin Carcinoma|Thyroid Gland Carcinoma|Uterine Corpus Cancer National Cancer Institute (NCI) August 12 2015 Phase 2
NCT02465060 Recruiting Advanced Malignant Solid Neoplasm|Bladder Carcinoma|Breast Carcinoma|Cervical Carcinoma|Colon Carcinoma|Colorectal Carcinoma|Endometrial Carcinoma|Esophageal Carcinoma|Gastric Carcinoma|Glioma|Head and Neck Carcinoma|Kidney Carcinoma|Liver and Intrahepatic Bile Duct Carcinoma|Lung Carcinoma|Lymphoma|Malignant Uterine Neoplasm|Melanoma|Ovarian Carcinoma|Pancreatic Carcinoma|Plasma Cell Myeloma|Prostate Carcinoma|Rectal Carcinoma|Recurrent Bladder Carcinoma|Recurrent Breast Carcinoma|Recurrent Cervical Carcinoma|Recurrent Colon Carcinoma|Recurrent Colorectal Carcinoma|Recurrent Esophageal Carcinoma|Recurrent Gastric Carcinoma|Recurrent Glioma|Recurrent Head and Neck Carcinoma|Recurrent Liver Carcinoma|Recurrent Lung Carcinoma|Recurrent Lymphoma|Recurrent Malignant Solid Neoplasm|Recurrent Melanoma|Recurrent Ovarian Carcinoma|Recurrent Pancreatic Carcinoma|Recurrent Plasma Cell Myeloma|Recurrent Prostate Carcinoma|Recurrent Rectal Carcinoma|Recurrent Skin Carcinoma|Recurrent Thyroid Gland Carcinoma|Recurrent Uterine Corpus Carcinoma|Refractory Lymphoma|Refractory Malignant Solid Neoplasm|Refractory Plasma Cell Myeloma|Skin Carcinoma|Thyroid Gland Carcinoma|Uterine Corpus Cancer National Cancer Institute (NCI) August 12 2015 Phase 2

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID