solo para uso en investigación

AZD4547 (Fexagratinib) FGFR Inhibidor

Name: AZD4547 (Fexagratinib)
Brand: Selleck Chemicals
SKU: S2801
Rating: 5 (147 reviews)

Cat. No.: S2801

Fexagratinib (AZD4547, ABSK 091) es un novedoso inhibidor selectivo de FGFR que actúa sobre FGFR1/2/3 con una IC50 de 0,2 nM/2,5 nM/1,8 nM en ensayos sin células, una actividad más débil contra FGFR4, VEGFR2(KDR) y poca actividad observada contra IGFR, CDK2 y p38. Fase 2/3.

AZD4547 (Fexagratinib) FGFR Inhibidor Chemical Structure

Estructura química

Peso molecular: 463.57

Saltar a

Control de calidad (Quality Control)

Lote: Pureza: 99.96%

99.96

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

Cultivo celular, tratamiento y concentración de trabajo
(Cell Culture, Treatment & Working Concentration)

Líneas celulares	Tipo de ensayo	Concentración	Tiempo de incubación	Descripción de la actividad	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
Haga clic para ver más datos experimentales de líneas celulares

Información química, almacenamiento y estabilidad (Chemical Information, Storage & Stability)

Peso molecular	463.57	Fórmula	C₂₆H₃₃N₅O₃	Almacenamiento (Desde la fecha de recepción)	3 años-20°Cpolvo
Nº CAS	1035270-39-3	Descargar SDF		Almacenamiento de soluciones madre	1 año-80°Cen disolvente 1 mes-20°Cen disolvente
Sinónimos	ABSK 091			Smiles	CC1CN(CC(N1)C)C2=CC=C(C=C2)C(=O)NC3=NNC(=C3)CCC4=CC(=CC(=C4)OC)OC

Solubilidad (Solubility)

In vitro
Lote:

DMSO : 93 mg/mL (200.61 mM)
(El DMSO contaminado con humedad puede reducir la solubilidad. Usar DMSO fresco y anhidro.)

Ethanol : 40 mg/mL

Water : Insoluble

Calculadora de Molaridad

Masa	Concentración	Volumen	Peso molecular
=	×	×

Calculadora de Dilución Calculadora de Peso Molecular

In vivo Lote:
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 Validado por los laboratorios Selleck. Si necesita ajustes en esta formulación, contacte con nuestro equipo de ventas para pruebas personalizadas.	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.

Calculadora de formulación in vivo (Solución clara)

Paso 1: Introduzca la información a continuación (Recomendado: Un animal adicional para tener en cuenta la pérdida durante el experimento)

Dosis: mg/kg Peso promedio de los animales: g Volumen de dosificación por animal:μL Número de animales:

Paso 2: Introduzca la formulación in vivo (Esto es solo la calculadora, no la formulación. Por favor, contáctenos primero si no hay una formulación in vivo en la sección de Solubilidad.)

% DMSO + % + % Tween 80 + % ddH₂O

%DMSO+ %

Resultados del cálculo:

Concentración de trabajo: mg/ml;

Método para preparar el líquido maestro de DMSO: mg fármaco predissuelto en μL DMSO ( Concentración del líquido maestro mg/mL, Por favor, contáctenos primero si la concentración excede la solubilidad del DMSO del lote del fármaco. )

Método para preparar la formulación in vivo: Tomar μL DMSO líquido maestro, luego añadirμL PEG300, mezclar y clarificar, luego añadirμL Tween 80, mezclar y clarificar, luego añadir μL ddH₂O, mezclar y clarificar.

Método para preparar la formulación in vivo: Tomar μL DMSO líquido maestro, luego añadir μL Aceite de maíz, mezclar y clarificar.

Nota: 1. Por favor, asegúrese de que el líquido esté claro antes de añadir el siguiente disolvente.
2. Asegúrese de añadir el (los) disolvente(s) en orden. Debe asegurarse de que la solución obtenida, en la adición anterior, sea una solución clara antes de proceder a añadir el siguiente disolvente. Se pueden utilizar métodos físicos como el vórtice, el ultrasonido o el baño de agua caliente para ayudar a la disolución.

Mecanismo de acción (Mechanism of Action)

Características	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	En comparación con FGFR1-3, AZD4547 muestra una actividad más débil contra FGFR4 con una IC50 de 165 nM. AZD4547 solo inhibe la actividad de la quinasa recombinante VEGFR2 (KDR) con una IC50 de 24 nM, en la prueba de selectividad in vitro contra un panel diverso de quinasas humanas representativas. AZD4547 a 0,1 μM no exhibe actividad contra una serie de quinasas recombinantes que incluyen ALK, CHK1, EGFR, MAPK1, MEK1, p70S6K, PDGFR, PKB, Src, Tie2 y PI3-quinasa. Consistentemente, la potente selectividad de AZD4547 para FGFR1-3 sobre FGFR4, IGFR y KDR también se observa en ensayos de fosforilación celular. AZD4547 tiene una potente actividad antiproliferativa in vitro solo contra líneas celulares tumorales que expresan FGFRs desregulados como KG1a, Sum52-PE y KMS11 con una IC50 de 18-281 nM, y es inactivo contra MCF7, así como más de 100 líneas celulares tumorales adicionales. El tratamiento con AZD4547 inhibe potentemente la fosforilación de FGFR y MAPK en líneas celulares tumorales humanas de manera dependiente de la dosis. AZD4547 también inhibe potentemente la fosforilación de FRS2 y PLCγ, marcadores descendentes de la señalización de FGFR. En particular, AZD4547 afecta la fosforilación de AKT en las líneas celulares mamarias, MCF7 y Sum52-PE, pero no en las líneas KG1a y KMS11. El tratamiento con AZD4547 induce significativamente la apoptosis en células Sum52-PE y KMS11, aumenta drásticamente la detención en G1 pero no la apoptosis en células KG1a, y no tiene efecto sobre la distribución del ciclo celular o la apoptosis en células MCF7.
Ensayo de quinasa	Actividad quinasa de AZD4547
Ensayo de quinasa	La capacidad de AZD4547 para inhibir las actividades quinasas recombinantes humanas de FGFR1-3 se prueba utilizando concentraciones de ATP iguales o ligeramente inferiores a las K_m respectivas.
In vivo	La administración oral de AZD4547 a 3 mg/kg dos veces al día en ratones con tumores KMS11 resulta en una inhibición significativa del crecimiento tumoral del 53% en comparación con los controles tratados con vehículo, y AZD4547 a 12,5 mg/kg una vez al día o 6,25 mg/kg dos veces al día conduce a una estasis tumoral completa, lo que se asocia con una modulación farmacodinámica proporcional a la dosis de phospho-FGFR3 y una proliferación reducida de células tumorales KMS11. Además, la administración oral de AZD4547 a 12,5 mg/kg una vez al día resulta en una inhibición del crecimiento tumoral del 65% en el modelo de xenoinjerto KG1a de fusión de FGFR1. A niveles de dosis eficaces, AZD4547 no exhibe efectos antiangiogénicos. AZD4547 no tiene un efecto significativo sobre la presión arterial y, por lo tanto, carece de actividad anti-KDR in vivo. Consistentemente, la administración de 6,25 mg/kg de AZD4547 por vía oral dos veces al día es inactiva en los modelos de xenoinjerto sensibles al cediranib, incluyendo Calu-6, HCT-15 y LoVo.
Referencias	[1] https://pubmed.ncbi.nlm.nih.gov/22369928/

Aplicaciones (Applications)

Métodos	Biomarcadores	Imágenes	PMID
Western blot	p-FGFR / FGFR1 / p-AKT / AKT / p-ERK / ERK pFRS2		28900173
Growth inhibition assay	Cell viability Cell viability		28900173

Información del ensayo clínico (Clinical Trial Information)

(datos de https://clinicaltrials.gov, actualizado el 2024-05-22)

Número NCT	Reclutamiento	Condiciones	Patrocinador/Colaboradores	Fecha de inicio	Fases
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

C1=C0/X	C1:	LOG(C1):
C2=C1/X	C2:	LOG(C2):
C3=C2/X	C3:	LOG(C3):
C4=C3/X	C4:	LOG(C4):
C5=C4/X	C5:	LOG(C5):
C6=C5/X	C6:	LOG(C6):
C7=C6/X	C7:	LOG(C7):
C8=C7/X	C8:	LOG(C8):