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AZD4547 (Fexagratinib) FGFR remmer

Name: AZD4547 (Fexagratinib)
Brand: Selleck Chemicals
SKU: S2801
Rating: 5 (146 reviews)

Cat.Nr.S2801

Fexagratinib (AZD4547,ABSK 091) is een nieuwe selectieve FGFR-remmer die zich richt op FGFR1/2/3 met een IC50 van 0,2 nM/2,5 nM/1,8 nM in celvrije assays, met een zwakkere activiteit tegen FGFR4, VEGFR2(KDR), en weinig activiteit waargenomen tegen IGFR, CDK2 en p38. Fase 2/3.

AZD4547 (Fexagratinib) FGFR remmer Chemical Structure

Chemische structuur

Moleculair gewicht: 463.57

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Kwaliteitscontrole

Batch: Zuiverheid: 99.96%

99.96

Gerelateerde doelwitten	EGFR VEGFR JAK PDGFR Src HIF FLT FLT3 HER2 Bcr-Abl
Overige FGFR Inhibitoren	PD173074 BLU9931 Futibatinib (TAS-120) LY2874455 PD-166866 Zoligratinib (Debio-1347) H3B-6527 Fisogatinib (BLU-554) SSR128129E Ferulic Acid

Celkweek, behandeling & werkconcentratie

Cellijnen	Assaytype	Concentratie	Incubatietijd	Activiteitsbeschrijving	PMID
SNU449	Growth Inhibition Assay		72 h	IC50=0.082 μM	26351320
SK-HEP-1	Growth Inhibition Assay		72 h	IC50=0.084 μM	26351320
SNU475	Growth Inhibition Assay		72 h	IC50=5.4 μM	26351320
Hep3B	Growth Inhibition Assay		72 h	IC50=6.43 μM	26351320
PLC/PRF5	Growth Inhibition Assay		72 h	IC50=6.55 μM	26351320
Hur7	Growth Inhibition Assay		72 h	IC50=7.25 μM	26351320
HepG2	Growth Inhibition Assay		72 h	IC50=8.73 μM	26351320
SNU449	Clonogenic assay	1 µM	24 h	decreases colony formation significantly	26351320
SK-HEP-1	Clonogenic assay	1 µM	24 h	decreases colony formation significantly	26351320
SNU449	Function Assay	0-2 μM	48 h	causes a decrease of FRS2，AKT, and ERK phosphorylation	26351320
SK-HEP-1	Function Assay	0-2 μM	48 h	causes a decrease of FRS2，AKT, and ERK phosphorylation	26351320
BaF3 FLT3-TEL	Growth Inhibition Assay			GI50=4.6 ± 0.577 μM	26294741
BaF3 RET-TEL	Growth Inhibition Assay			GI50=0.39 ± 0.048 μM	26294741
BaF3 Parental	Growth Inhibition Assay			GI50﹥10 μM	26294741
MOLM14 FLT3/ITD	Growth Inhibition Assay			GI50=0.484 ± 0.157 μM	26294741
MV4-11 FLT3/ITD	Growth Inhibition Assay			GI50=0.459 ± 0.046 μM	26294741
TT RET C634W	Growth Inhibition Assay			GI50=2.9 ± 0.904 μM	26294741
AN3-CA FGFR2 N550K, K310R	Growth Inhibition Assay			GI50=0.031 ± 0.023 μM	26294741
MFE296 FGFR2 N550K	Growth Inhibition Assay			GI50=0.730 ± 0.057 μM	26294741
MFE280 FGFR2 S252W	Growth Inhibition Assay			GI50=0.218 ± 0.073 μM	26294741
Ishikawa FGFF2 over exp.	Growth Inhibition Assay			GI50=4.5 ± 1.51 μM	26294741
HEC1A Normal FGFR2	Growth Inhibition Assay			GI50﹥10 μM	26294741
A549	Cell viability Assay	0.1/1 μM	48 h	enhances Erlotinib induced viability loss	26053020
SGC-7901	Growth Inhibition Assay	1 nM-10 μM	72 h	IC50 of 5-10 μM, inhibits cell viability dose dependently	25576915
HGC-27	Growth Inhibition Assay	1 nM-10 μM	72 h	IC50 of 5-10 μM, inhibits cell viability dose dependently	25576915
MKN-28	Growth Inhibition Assay	1 nM-10 μM	72 h	IC50 of 5-10 μM, inhibits cell viability dose dependently	25576915
NCI-N87	Growth Inhibition Assay	1 nM-10 μM	72 h	IC50 of 5-10 μM, inhibits cell viability dose dependently	25576915
KATOIII	Growth Inhibition Assay	1 nM-10 μM	72 h	IC50 of 10-100 nM, inhibits cell viability dose dependently	25576915
SNU-16	Growth Inhibition Assay	1 nM-10 μM	72 h	IC50 of 10-100 nM, inhibits cell viability dose dependently	25576915
4T1	Growth Inhibition Assay			IC50=0.64±0.11 μM	24642893
MDA-MB-468	Growth Inhibition Assay			IC50=4.9±0.85 μM	24642893
HCT116	Growth Inhibition Assay			IC50=15.9±1.82 μM	24642893
SW620	Growth Inhibition Assay			IC50＞20 μM	24642893
MDA-MB-231	Growth Inhibition Assay			IC50＞20 μM	24642893
CT26	Growth Inhibition Assay			IC50＞20 μM	24642893
SW480	Growth Inhibition Assay			IC50＞20 μM	24642893
4T1	Apoptosis Assay	1.25-20 μM	24 h	induces apoptosis dose dependently	24642893
KG1a	Growth Inhibition Assay			IC50=0.018 μM	22369928
Sum52-PE	Growth Inhibition Assay			IC50=0.041 μM	22369928
KMS11	Growth Inhibition Assay			IC50=0.281 μM	22369928
MCF7	Growth Inhibition Assay			IC50>30 μM	22369928
KG1	Function assay		72 hrs	Inhibition of FGFR1 in human KG1 cells assessed as suppression of cell proliferation after 72 hrs by SRB/CCK-8 assay, IC50 = 0.0002 μM.	27117427
RT112	Function assay		72 hrs	Inhibition of FGFR3 in human RT112 cells assessed as suppression of cell proliferation after 72 hrs by SRB/CCK-8 assay, IC50 = 0.0006 μM.	27117427
KG1	Antiproliferative assay		72 hrs	Antiproliferative activity against human KG1 cells expressing FGFR1 after 72 hrs, IC50 = 0.0019 μM.	29775937
KG1	Antiproliferative assay		72 hrs	Antiproliferative activity against human KG1 cells after 72 hrs by CCK-8 assay, IC50 = 0.0033 μM.	28687204
SNU16	Antiproliferative assay		72 hrs	Antiproliferative activity against human SNU16 cells after 72 hrs by CCK-8 assay, IC50 = 0.0034 μM.	28687204
SNU16	Function assay		72 hrs	Inhibition of recombinant FGFR2 in human SNU16 cells assessed as suppression of cell proliferation after 72 hrs by SRB/CCK-8 assay, IC50 = 0.0036 μM.	27117427
SNU16	Antiproliferative assay		72 hrs	Antiproliferative activity against human SNU16 cells expressing FGFR2 after 72 hrs, IC50 = 0.0062 μM.	29775937
KG1	Antiproliferative assay		72 hrs	Antiproliferative activity against FGFR1-translocated human KG1 cells after 72 hrs by CCK8/MTT assay, IC50 = 0.0064 μM.	27348537
SNU16	Antiproliferative assay		72 hrs	Antiproliferative activity against FGFR2-amplified human SNU16 cells after 72 hrs by CCK8/MTT assay, IC50 = 0.0134 μM.	27348537
KATO III	Function assay		72 hrs	Inhibition of FGFR2 in human KATO III cells assessed as inhibition of cell proliferation after 72 hrs by cell counting kit-8 assay, IC50 = 0.0141 μM.	28714692
KG1	Function assay		72 hrs	Inhibition of FGFR1OP2 fused FGFR1 in human KG1 cells assessed as inhibition of cell proliferation after 72 hrs by cell counting kit-8 assay, IC50 = 0.0161 μM.	28714692
KATO III	Function assay		72 hrs	Inhibition of FGFR2 in human KATO III cells assessed as suppression of cell proliferation after 72 hrs by SRB/CCK-8 assay, IC50 = 0.0202 μM.	27117427
SNU16	Function assay		72 hrs	Inhibition of FGFR2 in human SNU16 cells assessed as inhibition of cell proliferation after 72 hrs by cell counting kit-8 assay, IC50 = 0.0254 μM.	28714692
UM-UC-14	Antiproliferative assay		72 hrs	Antiproliferative activity against human UM-UC-14 cells expressing FGFR3 after 72 hrs, IC50 = 0.0269 μM.	29775937
RT112	Function assay		72 hrs	Inhibition of FGFR3 in human RT112 cells assessed as inhibition of cell proliferation after 72 hrs by cell counting kit-8 assay, IC50 = 0.027 μM.	28714692
UM-UC-14	Function assay		72 hrs	Inhibition of FGFR3 mutant in human UM-UC-14 cells assessed as inhibition of cell proliferation after 72 hrs by cell counting kit-8 assay, IC50 = 0.0271 μM.	28714692
RT112	Antiproliferative assay		72 hrs	Antiproliferative activity against human RT112 cells after 72 hrs by MTT assay, GI50 = 0.0292 μM.	27599742
H1581	Function assay		72 hrs	Inhibition of FGFR1 in human H1581 cells assessed as suppression of cell proliferation after 72 hrs by SRB/CCK-8 assay, IC50 = 0.0329 μM.	27117427
NCI-H1581	Antiproliferative assay		72 hrs	Antiproliferative activity against human NCI-H1581 cells expressing FGFR1 after 72 hrs, IC50 = 0.04 μM.	29775937
B16F10	Cytotoxicity assay		72 hrs	Cytotoxicity against mouse B16F10 cells after 72 hrs by MTT assay, IC50 = 0.051 μM.	25736993
A549	Cytotoxicity assay		72 hrs	Cytotoxicity against human A549 cells after 72 hrs by MTT assay, IC50 = 0.062 μM.	25736993
NCI-H1581	Function assay		72 hrs	Inhibition of FGFR1 in human NCI-H1581 cells assessed as inhibition of cell proliferation after 72 hrs by cell counting kit-8 assay, IC50 = 0.0626 μM.	28714692
RT112	Antiproliferative assay		72 hrs	Antiproliferative activity against human RT112 cells expressing FGFR3 after 72 hrs, IC50 = 0.0838 μM.	29775937
RT112	Antiproliferative assay		72 hrs	Antiproliferative activity against FGFR3-amplified human RT112 cells after 72 hrs by CCK8/MTT assay, IC50 = 0.0884 μM.	27348537
NCI-H1581	Antiproliferative assay		72 hrs	Antiproliferative activity against FGFR1-amplified human NCI-H1581 cells after 72 hrs by CCK8/MTT assay, IC50 = 0.0921 μM.	27348537
HeLa 229	Cytotoxicity assay		72 hrs	Cytotoxicity against human HeLa 229 cells after 72 hrs by MTT assay, IC50 = 0.14 μM.	25736993
BAF3	Antiproliferative assay		72 hrs	Antiproliferative activity against mouse BAF3 cells expressing VEGFR2 after 72 hrs, IC50 = 0.222 μM.	29775937
SGC7901	Antiproliferative assay		72 hrs	Antiproliferative activity against human SGC7901 cells after 72 hrs by MTT assay, IC50 = 2.8 μM.	27829519
MGC803	Antiproliferative assay		72 hrs	Antiproliferative activity against human MGC803 cells after 72 hrs by MTT assay, IC50 = 6.2 μM.	27829519
BGC823	Antiproliferative assay		72 hrs	Antiproliferative activity against human BGC823 cells after 72 hrs by MTT assay, IC50 = 7.9 μM.	27829519
HL7702	Cytotoxicity assay		72 hrs	Cytotoxicity against human HL7702 cells after 72 hrs by MTT assay, IC50 = 18.21 μM.	25736993
U-2 OS	qHTS ssay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for U-2 OS cells	29435139
A673	qHTS ssay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for A673 cells	29435139
Saos-2	qHTS ssay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Saos-2 cells	29435139
BT-37	qHTS ssay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for BT-37 cells	29435139
RD	qHTS ssay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for RD cells	29435139
SK-N-SH	qHTS ssay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SK-N-SH cells	29435139
BT-12	qHTS ssay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for BT-12 cells	29435139
OHS-50	qHTS ssay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for OHS-50 cells	29435139
fibroblast cells	qHTS ssay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for control Hh wild type fibroblast cells	29435139
Rh41	qHTS ssay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Rh41 cells	29435139
Rh30	qHTS ssay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Rh30 cells	29435139
SJ-GBM2	qHTS ssay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SJ-GBM2 cells	29435139
NB-EBc1	qHTS ssay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for NB-EBc1 cells	29435139
LAN-5	qHTS ssay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for LAN-5 cells	29435139
Rh18	qHTS ssay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Rh18 cells	29435139
Klik om meer experimentele gegevens over de cellijn te bekijken

Chemische informatie, Opslag en Stabiliteit

Moleculair gewicht	463.57	Formule	C₂₆H₃₃N₅O₃	Opslag (Vanaf de ontvangstdatum)	3 jaar-20°Cpoeder
CAS-nr.	1035270-39-3	SDF downloaden		Opslag van stamoplossingen	1 jaar-80°Cin oplosmiddel 1 maand-20°Cin oplosmiddel
Synoniemen	ABSK 091			Smiles	CC1CN(CC(N1)C)C2=CC=C(C=C2)C(=O)NC3=NNC(=C3)CCC4=CC(=CC(=C4)OC)OC

Oplosbaarheid

In vitro
Batch:

DMSO : 93 mg/mL (200.61 mM)
(Met vocht verontreinigde DMSO kan de oplosbaarheid verminderen. Gebruik verse, watervrije DMSO.)

Ethanol : 40 mg/mL

Water : Insoluble

Molariteitscalculator

Massa	Concentratie	Volume	Moleculair gewicht
=	×	×

Verdunningscalculator Moleculair gewicht calculator

In vivo Batch:
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Clear solution	4%DMSO 1 30%PEG300 2 5%Tween80 3 61%ddH2O Gevalideerd door Selleck labs. Mocht u aanpassingen aan deze formulering nodig hebben, neem dan contact op met ons verkoopteam voor aangepaste tests.	5.000mg/ml (10.79mM)	Taking the 1 mL working solution as an example, add 40 μL of 125 mg/ml clarified DMSO stock solution to 300 μL of PEG300, mix evenly to clarify it; add 50 μL of Tween80 to the above system, mix evenly to clarify it; then continue to add 610 μL of ddH2O to adjust the volume to 1 mL. The mixed solution should be used immediately for optimal results.
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.

In vivo Formuleringscalculator (Heldere oplossing)

Stap 1: Voer de onderstaande informatie in (Aanbevolen: Een extra dier voor het geval van verlies tijdens het experiment)

Dosering: mg/kg Gemiddeld gewicht van dieren: g Doseervolume per dier:μL Aantal dieren:

Stap 2: Voer de in vivo formulering in (Dit is alleen de calculator, geen formulering. Neem eerst contact met ons op als er geen in vivo formulering is in het gedeelte Oplosbaarheid.)

% DMSO + % + % Tween 80 + % ddH₂O

%DMSO+ %

Berekeningsresultaten:

Werkconcentratie: mg/ml;

Methode voor het bereiden van DMSO-mastervloeistof: mg geneesmiddel vooraf opgelost in μL DMSO ( Concentratie mastervloeistof mg/mL, Neem eerst contact met ons op als de concentratie de DMSO-oplosbaarheid van de partij geneesmiddel overschrijdt. )

Methode voor het bereiden van in vivo formulering: Neem μL DMSO mastervloeistof, voeg vervolgens toeμL PEG300, mengen en helder maken, voeg vervolgens toeμL Tween 80, mengen en helder maken, voeg vervolgens toe μL ddH₂O, mengen en helder maken.

Methode voor het bereiden van in vivo formulering: Neem μL DMSO mastervloeistof, voeg vervolgens toe μL Maïsolie, mengen en helder maken.

Opmerking: 1. Zorg ervoor dat de vloeistof helder is voordat u het volgende oplosmiddel toevoegt.
2. Zorg ervoor dat u het/de oplosmiddel(en) in de juiste volgorde toevoegt. U moet ervoor zorgen dat de verkregen oplossing, bij de vorige toevoeging, een heldere oplossing is voordat u verdergaat met het toevoegen van het volgende oplosmiddel. Fysische methoden zoals vortexen, echografie of een warmwaterbad kunnen worden gebruikt om het oplossen te bevorderen.

Werkingsmechanisme

Kenmerken	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/IC₅₀/Ki	FGFR1 (Cell-free assay) 0.2 nM FGFR3 (Cell-free assay) 1.8 nM FGFR2 (Cell-free assay) 2.5 nM KDR (Cell-free assay) 24 nM
In vitro	Vergeleken met FGFR1-3 vertoont AZD4547 een zwakkere activiteit tegen FGFR4 met een IC50 van 165 nM. AZD4547 remt alleen de recombinante VEGFR2 (KDR) kinaseactiviteit met een IC50 van 24 nM, in de in vitro selectiviteitstest tegen een divers panel van representatieve menselijke kinasen. AZD4547 bij 0,1 μM vertoont geen activiteit tegen een reeks recombinante kinasen waaronder ALK, CHK1, EGFR, MAPK1, MEK1, p70S6K, PDGFR, PKB, Src, Tie2 en PI3-kinase. Consistent hiermee wordt de potente selectiviteit van AZD4547 voor FGFR1-3 boven FGFR4, IGFR en KDR ook waargenomen in cellulaire fosforyleringsassays. AZD4547 heeft een potente in vitro antiproliferatieve activiteit alleen tegen tumorcellijnen die gedereguleerde FGFR's tot expressie brengen, zoals KG1a, Sum52-PE en KMS11 met een IC50 van 18-281 nM, en is inactief tegen MCF7 en meer dan 100 andere tumorcellijnen. AZD4547-behandeling remt potent de FGFR- en MAPK-fosforylering in menselijke tumorcellijnen op een dosisafhankelijke manier. AZD4547 remt ook potent de fosforylering van FRS2 en PLCγ, downstream markers van FGFR-signalering. Met name beïnvloedt AZD4547 de AKT-fosforylering in de borstcellijnen MCF7 en Sum52-PE, maar niet in KG1a- en KMS11-lijnen. AZD4547-behandeling induceert significant apoptose in Sum52-PE- en KMS11-cellen, verhoogt drastisch de G1-arrestatie maar niet de apoptose in KG1a-cellen, en heeft geen effect op de celcyclusdistributie of apoptose in MCF7-cellen.
Kinase Assay	AZD4547 kinaseactiviteit
Kinase Assay	Het vermogen van AZD4547 om de humane recombinante kinaseactiviteiten van FGFR1-3 te remmen, wordt getest met ATP-concentraties op, of net onder, de respectieve K_m.
In vivo	Orale toediening van AZD4547 aan 3 mg/kg tweemaal daags bij muizen met KMS11-tumoren resulteert in een significante tumorremming van 53% vergeleken met voertuigbehandelde controles, en AZD4547 aan 12,5 mg/kg eenmaal daags of 6,25 mg/kg tweemaal daags leidt tot complete tumorstase, wat geassocieerd is met dosisproportionele farmacodynamische modulatie van phospho-FGFR3 en verminderde KMS11 tumorcelproliferatie. Bovendien resulteert orale toediening van AZD4547 aan 12,5 mg/kg eenmaal daags in 65% tumorremming in het FGFR1-fusie KG1a xenograftmodel. Bij effectieve dosisniveaus vertoont AZD4547 geen anti-angiogene effecten. AZD4547 heeft geen significant effect op de bloeddruk en mist daarom in vivo anti-KDR activiteit. Consistent hiermee is de dosering van 6,25 mg/kg oraal tweemaal daags AZD4547 inactief in de cediranib-gevoelige xenograftmodellen waaronder Calu-6, HCT-15 en LoVo.
Referenties	[1] https://pubmed.ncbi.nlm.nih.gov/22369928/

Toepassingen

Methoden	Biomarkers	Afbeeldingen	PMID
Western blot	p-FGFR / FGFR1 / p-AKT / AKT / p-ERK / ERK pFRS2		28900173
Growth inhibition assay	Cell viability Cell viability		28900173

Informatie klinische proef

(gegevens van https://clinicaltrials.gov, bijgewerkt op 2024-05-22)

NCT-nummer	Rekrutering	Aandoeningen	Sponsor/Medewerkers	Startdatum	Fasen
NCT02824133	Completed	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
NCT01824901	Completed	Recurrent Non-small Cell Lung Cancer\|Squamous Cell Lung Cancer	ECOG-ACRIN Cancer Research Group\|National Cancer Institute (NCI)\|Eastern Cooperative Oncology Group	January 15 2014	Phase 1\|Phase 2
NCT01795768	Unknown status	Gastric Cancer\|Oesophageal Cancer\|Breast Cancer\|Squamous Cell Carcinoma of the Lung	Royal Marsden NHS Foundation Trust\|AstraZeneca	September 2012	Phase 2
NCT01213160	Completed	Cancer\|Advanced Solid Malignancies	AstraZeneca	November 2010	Phase 1

Technische ondersteuning

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Tel: +1-832-582-8158 Ext:3

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