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AZD1480 JAK inhibiteur

Name: AZD1480
Brand: Selleck Chemicals
SKU: S2162
Rating: 5 (123 reviews)

N° Cat.S2162

L'AZD1480 est un nouvel inhibiteur ATP-compétitif de JAK2 avec une IC50 de 0,26 nM dans un essai acellulaire, une sélectivité contre JAK3 et Tyk2, et dans une moindre mesure contre JAK1. Phase 1.

AZD1480 JAK inhibiteur Chemical Structure

Structure chimique

Poids moléculaire: 348.77

Aller à

Contrôle qualité

Lot : Pureté : 99.16%

99.16

Cibles apparentées	EGFR STAT Pim
Autre JAK Inhibiteurs	BMS-986165 (Deucravacitinib) WP1066 Momelotinib (CYT387) Filgotinib (GLPG0634) AT9283 Gandotinib (LY2784544) Pacritinib TG101209 Cerdulatinib (PRT062070) hydrochloride NVP-BSK805 2HCl

Culture cellulaire, traitement et concentration de travail

Lignées cellulaires	Type dessai	Concentration	Temps dincubation	Formulation	Description de lactivité	PMID
SW620	Function Assay	5 μM	48 h	DMSO	blocks JAK2/STAT3 signaling	25954974
LoVo	Function Assay	5 μM	48 h	DMSO	blocks JAK2/STAT3 signaling	25954974
HN5	Growth Inhibition Assay		72 h		EC50=3.81 ± 1.99 μM	25810010
Cal33	Growth Inhibition Assay		72 h		EC50=3.37 ± 0.75 μM	25810010
UM-22B	Growth Inhibition Assay		72 h		EC50=2.66 ± 0.24 μM	25810010
686LN	Growth Inhibition Assay		72 h		EC50=2.05 ± 1.33 μM	25810010
UM SCC-1	Growth Inhibition Assay		72 h		EC50=1.67 ± 0.42 μM	25810010
UM-22A	Growth Inhibition Assay		72 h		EC50=1.32 ± 0.39 μM	25810010
OSC19	Growth Inhibition Assay		72 h		EC50=1.26 ± 0.20 μM	25810010
PCI-52	Growth Inhibition Assay		72 h		EC50=1.00 ± 0.09 μM	25810010
PCI-15B	Growth Inhibition Assay		72 h		EC50=0.99 ± 1.74 μM	25810010
UMSCC-1	Function Assay	0.0005-1.6 μM	24 h		abrogates IL-6–induced up-regulation of pSTAT3Tyr705 in a dose-dependent manner	25810010
Cal33	Function Assay	0.0005-3.8 μM	24 h		abrogates IL-6–induced up-regulation of pSTAT3Tyr705 in a dose-dependent manner	25810010
HH5	Function Assay	0.0005-3.8 μM	24 h		abrogates IL-6–induced up-regulation of pSTAT3Tyr705 in a dose-dependent manner	25810010
UM-22A	Function Assay	0.0005-1.6 μM	24 h		abrogates IL-6–induced up-regulation of pSTAT3Tyr705 in a dose-dependent manner	25810010
A1847	Function Assay	0.05-10 μM	24 h	DMSO	reduces phosphorylated STAT3 levels	25646015
OVCAR-5	Function Assay	0.05-10 μM	24 h	DMSO	reduces phosphorylated STAT3 levels	25646015
OVCAR-8	Function Assay	0.05-10 μM	24 h	DMSO	reduces phosphorylated STAT3 levels	25646015
MOVCAR-5447	Function Assay	0.05-10 μM	24 h	DMSO	reduces phosphorylated STAT3 levels	25646015
MOVCAR-5009	Function Assay	0.05-10 μM	24 h	DMSO	reduces phosphorylated STAT3 levels	25646015
A1847	Cell Viability Assay	0.05-10 μM	72 h	DMSO	reduces cell viability at the concerntration of 5 μM	25646015
OVCAR-5	Cell Viability Assay	0.05-10 μM	72 h	DMSO	reduces cell viability at the concerntration of 5 μM	25646015
OVCAR-8	Cell Viability Assay	0.05-10 μM	72 h	DMSO	reduces cell viability at the concerntration of 5 μM	25646015
OVCAR-5	Apoptosis Assay	0.5/1/5 μM	48 h	DMSO	induces significant apoptosis at high concerntration	25646015
OVCAR-8	Apoptosis Assay	0.5/1/5 μM	48 h	DMSO	induces significant apoptosis at high concerntration	25646015
AKRSL	Cell Viability Assay		72 h		IC50＞10 μM	25504635
PALJDL	Cell Viability Assay		72 h		IC50=2.4 μM	25504635
MO4	Function Assay	0.5/1/5 μM	6 h		inhibits P-STAT3 expression	25149535
DU145	Function Assay	0-200 nM	1 h		suppresses IL-6-activated Stat3 and ERK1/2 signaling	24577942
DU145	Function Assay	800 nM	72 h		suppresses IL-6-induced migratory	24577942
CWR22Rv1	Function Assay	800 nM	72 h		suppresses IL-6-induced migratory	24577942
N592	Growth Inhibition Assay				IC50=0.84 μM	24158701
H82	Growth Inhibition Assay				IC50=1.37 μM	24158701
GLC4	Growth Inhibition Assay				IC50=1.79 μM	24158701
H526	Growth Inhibition Assay				IC50=3.08 μM	24158701
H1173	Growth Inhibition Assay				IC50=2.39 μM	24158701
DMS114	Growth Inhibition Assay				IC50=0.73 μM	24158701
NCI-N592	Function Assay	0.3/1/3 μM	24 h		induces G2/M cell cycle arrest	24158701
GLC4	Function Assay	0.3/1/3 μM	24 h		induces G2/M cell cycle arrest	24158701
NCI-H82	Function Assay	0.3/1/3 μM	24 h		induces G2/M cell cycle arrest	24158701
NCI-N592	Apoptosis Assay	0.3/1/3 μM	48 h		increases the level of cleaved-Caspase 3	24158701
GLC4	Apoptosis Assay	0.3/1/3 μM	48 h		increases the level of cleaved-Caspase 3	24158701
NCI-H82	Apoptosis Assay	0.3/1/3 μM	48 h		increases the level of cleaved-Caspase 3	24158701
CWR22Rv1	Apoptosis Assay				IC50=0.482 μM	23942095
CWR22Pc	Apoptosis Assay				IC50=0.438 μM	23942095
PC-3	Apoptosis Assay				IC50=1.755 μM	23942095
DU145	Apoptosis Assay				IC50=3.517 μM	23942095
RC165N	Apoptosis Assay				IC50=2.083 μM	23942095
ARPE19	Growth Inhibition Assay			DMSO	IC50=24.38 μM	23531921
HEK293	Growth Inhibition Assay			DMSO	IC50=8.67 μM	23531921
KCNR	Growth Inhibition Assay			DMSO	IC50=0.46 μM	23531921
SY5Y	Growth Inhibition Assay			DMSO	IC50=0.36 μM	23531921
BE2	Growth Inhibition Assay			DMSO	IC50=0.71 μM	23531921
AS	Growth Inhibition Assay			DMSO	IC50=1.53 μM	23531921
NGP	Growth Inhibition Assay			DMSO	IC50=0.56 μM	23531921
IMR32	Growth Inhibition Assay			DMSO	IC50=0.66 μM	23531921
LAN5	Growth Inhibition Assay			DMSO	IC50=1.04 μM	23531921
RH18	Growth Inhibition Assay			DMSO	IC50=1.42 μM	23531921
RH30	Growth Inhibition Assay			DMSO	IC50=1.25 μM	23531921
RH17	Growth Inhibition Assay			DMSO	IC50=2.51 μM	23531921
RH28	Growth Inhibition Assay			DMSO	IC50=4.28 μM	23531921
RH36	Growth Inhibition Assay			DMSO	IC50=5.37 μM	23531921
RH41	Growth Inhibition Assay			DMSO	IC50=0.48 μM	23531921
RD	Growth Inhibition Assay			DMSO	IC50=4.32 μM	23531921
TC32	Growth Inhibition Assay			DMSO	IC50=3.85 μM	23531921
TC71	Growth Inhibition Assay			DMSO	IC50=4.33 μM	23531921
KCNR	Apoptosis Assay	0.5/1.0/2.5 μM	24 h	DMSO	induces an increase in caspase 3/7 activity	23531921
SY5Y	Apoptosis Assay	0.5/1.0/2.5 μM	24 h	DMSO	induces an increase in caspase 3/7 activity	23531921
Rh18	Apoptosis Assay	0.5/1.0/2.5 μM	24 h	DMSO	induces an increase in caspase 3/7 activity	23531921
TC32	Apoptosis Assay	0.5/1.0/2.5 μM	24 h	DMSO	induces an increase in caspase 3/7 activity	23531921
KCNR	Function Assay	0.5/1.0/2.5/5 μM	24 h	DMSO	inhibits both endogenous constitutive and IL-6-induced STAT3 activation	23531921
SY5Y	Function Assay	0.5/1.0/2.5/5 μM	24 h	DMSO	inhibits both endogenous constitutive and IL-6-induced STAT3 activation	23531921
Rh18	Function Assay	0.5/1.0/2.5/5 μM	24 h	DMSO	inhibits both endogenous constitutive and IL-6-induced STAT3 activation	23531921
TC32	Function Assay	0.5/1.0/2.5/5 μM	24 h	DMSO	inhibits both endogenous constitutive and IL-6-induced STAT3 activation	23531921
TPC-1	Growth Inhibition Assay	1 µM	0-4 d	DMSO	inhibits cell growth after 2 d treatment	23056499
MZ-CRC1	Growth Inhibition Assay	1 µM	0-5 d	DMSO	inhibits cell growth after 1 d treatment	23056499
TT	Growth Inhibition Assay	1 µM	0-4 d	DMSO	inhibits cell growth after 1 d treatment	23056499
TPC-1	Function Assay	1 µM	72 h	DMSO	induces G1 blockage	23056499
MZ-CRC1	Function Assay	1 µM	72 h	DMSO	induces G1 blockage	23056499
TT	Function Assay	1 µM	72 h	DMSO	induces G1 blockage	23056499
MZ-CRC1	Apoptosis Assay	1 µM	48 h	DMSO	induces apoptosis	23056499
TT	Apoptosis Assay	1 µM	48 h	DMSO	induces apoptosis	23056499
HD-LM2	Growth Inhibition Assay		72 h	DMSO	IC50=7.844 μM	22829094
L-428	Growth Inhibition Assay		72 h	DMSO	IC50=7.947 μM	22829094
KM-H2	Growth Inhibition Assay		72 h	DMSO	IC50=1.308 μM	22829094
L-540	Growth Inhibition Assay		72 h	DMSO	IC50=8.216 μM	22829094
HD-LM2	Function Assay	0.1/0.5/1/5 μM	72 h	DMSO	inhibits STAT3, STAT5 and STAT6 phosphorylation	22829094
L-428	Function Assay	0.1/0.5/1/5 μM	72 h	DMSO	inhibits STAT3, STAT5 and STAT6 phosphorylation	22829094
KM-H2	Function Assay	0.1/0.5/1/5 μM	72 h	DMSO	inhibits STAT3, STAT5 and STAT6 phosphorylation	22829094
L-540	Function Assay	0.1/0.5/1/5 μM	72 h	DMSO	inhibits STAT3, STAT5 and STAT6 phosphorylation	22829094
HD-LM2	Apoptosis Assay	1/5 μM	72 h	DMSO	induces apoptosis	22829094
L-428	Apoptosis Assay	1/5 μM	72 h	DMSO	induces apoptosis	22829094
KM-H2	Apoptosis Assay	1/5 μM	72 h	DMSO	induces apoptosis	22829094
L-540	Apoptosis Assay	1/5 μM	72 h	DMSO	induces apoptosis	22829094
U251-MG	Function Assay	1 µM	0-16 h		inhibits constitutive STAT-3 and JAK2 activation	22027691
U87-MG	Function Assay	1 µM	0-16 h		inhibits constitutive STAT-3 and JAK2 activation	22027691
4C8	Function Assay	1 µM	0-16 h		inhibits constitutive STAT-3 and JAK2 activation	22027691
U251-MG	Growth Inhibition Assay	1/10 µM	24/48/72 h		inhibits cell proliferation at a concentration of 10 µM	22027691
U87-MG	Growth Inhibition Assay	1/10 µM	24/48/72 h		inhibits cell proliferation at a concentration of 10 µM	22027691
4C8	Growth Inhibition Assay	1/10 µM	24/48/72 h		inhibits cell proliferation at a concentration of 10 µM	22027691
U266	Apoptosis Assay	0.5-2 μM	48/72 h		induces apoptosis dose dependently	21164517
Kms.11	Apoptosis Assay	0.5-2 μM	48/72 h		induces apoptosis dose dependently	21164517
8226	Apoptosis Assay	0.5-2 μM	48/72 h		induces apoptosis dose dependently	21164517
SET2	Growth inhibition assay		48 hrs		Growth inhibition of human SET2 cells expressing Jak2 V617F mutant after 48 hrs by MTS assay, GI50 = 0.016 μM.	21138246
SET2	Function assay		1 hr		Inhibition of Stat3 phosphorylation in human SET2 cells after 1 hr by Western blotting, IC50 = 0.023 μM.	21138246
SET2	Function assay		1 hr		Inhibition of Stat5 phosphorylation in human SET2 cells after 1 hr by Western blotting, IC50 = 0.025 μM.	21138246
HEL	Function assay		1 hr		Inhibition of Stat5 phosphorylation in human HEL cells after 1 hr by Western blotting, IC50 = 0.041 μM.	21138246
Ba/F3	Function assay				Inhibition of Stat5 phosphorylation in mouse Ba/F3 cells expressing TEL-Jak2, IC50 = 0.046 μM.	21138246
UKE1	Growth inhibition assay		48 hrs		Growth inhibition of human UKE1 cells expressing Jak2 V617F mutant after 48 hrs by MTS assay, GI50 = 0.054 μM.	21138246
BA/F3	Growth inhibition assay		48 hrs		Growth inhibition of mouse BA/F3 cells expressing Tel-JAK2 kinase after 48 hrs by MTS assay, GI50 = 0.06 μM.	21138246
HEL	Function assay		1 hr		Inhibition of Stat3 phosphorylation in human HEL cells after 1 hr by Western blotting, IC50 = 0.08 μM.	21138246
HEL	Growth inhibition assay		48 hrs		Growth inhibition of human HEL cells expressing Jak2 V617F mutant after 48 hrs by MTS assay, GI50 = 0.39 μM.	21138246
BA/F3	Growth inhibition assay		48 hrs		Growth inhibition of mouse BA/F3 cells expressing Tel-JAK1 kinase after 48 hrs by MTS assay, GI50 = 0.7 μM.	21138246
BA/F3	Growth inhibition assay		48 hrs		Growth inhibition of mouse BA/F3 cells expressing Tel-Tyk2 kinase after 48 hrs by MTS assay, GI50 = 2 μM.	21138246
BA/F3	Growth inhibition assay		48 hrs		Growth inhibition of mouse BA/F3 cells expressing Tel-JAK3 kinase after 48 hrs by MTS assay, GI50 = 2.1 μM.	21138246
UKE1	Function assay		1 hr		Inhibition of Stat5 phosphorylation in human UKE1 cells after 1 hr by Western blotting	21138246
SW620	Cell cycle assay	3.3 uM	24 hrs		Cell cycle arrest in human SW620 cells assessed as accumulation at G2/M phase at 3.3 uM after 24 hrs by flow cytometry	21138246
HEL	Function assay	0.3 uM	5 mins		Inhibition of Stat5 phosphorylation in human HEL cells at 0.3 uM after 5 mins by Western blotting	21138246
HEL	Function assay	0.3 uM	30 to 60 mins		Inhibition of Stat5 phosphorylation in human HEL cells at 0.3 uM after 30 to 60 mins by Western blotting	21138246
BA/F3	Antitumor assay	30 mg/kg	12 hrs		Antitumor activity against mouse BA/F3 cells expressing Tel-JAK2 xenografted in NCr mouse assessed as reduction of phosphorylated Stat5 level in spleen at 30 mg/kg, po after 12 hrs by Western blotting	21138246
HEL	Function assay	0.3 uM	5 mins		Inhibition of Stat3 phosphorylation in human HEL cells at 0.3 uM after 5 mins by Western blotting	21138246
HEL	Function assay	0.3 uM	30 to 60 mins		Inhibition of Stat3 phosphorylation in human HEL cells at 0.3 uM after 30 to 60 mins by Western blotting	21138246
Hs578T	Function assay	1 uM	24 hrs		Inhibition of STAT3C-mediated transcription in human Hs578T cells at 1 uM after 24 hrs by luciferase reporter gene assay	24978112
NCI-H1975	Function assay	0.003 to 3 uM	2 hrs		Inhibition of JAK1 in human NCI-H1975 cells assessed as reduction in STAT3 phosphorylation at 0.003 to 3 uM after 2 hrs by Western blot analysis	26614408
HEL 92.1.7	Function assay		2 hrs		Inhibition of JAK2 in human HEL 92.1.7 cells assessed as reduction in STAT5 phosphorylation after 2 hrs by Western blot analysis	26614408
DAOY	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for DAOY cells	29435139
SJ-GBM2	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SJ-GBM2 cells	29435139
A673	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for A673 cells	29435139
SK-N-MC	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SK-N-MC cells	29435139
BT-37	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for BT-37 cells	29435139
NB-EBc1	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for NB-EBc1 cells	29435139
Saos-2	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Saos-2 cells	29435139
SK-N-SH	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SK-N-SH cells	29435139
NB1643	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for NB1643 cells	29435139
BT-12	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for BT-12 cells	29435139
OHS-50	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for OHS-50 cells	29435139
RD	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for RD cells	29435139
MG 63 (6-TG R)	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for MG 63 (6-TG R) cells	29435139
Rh41	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Rh41 cells	29435139
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Informations chimiques, stockage et stabilité

Poids moléculaire	348.77	Formule	C₁₄H₁₄ClFN₈	Stockage (À partir de la date de réception)	3 ans-20°Cpoudre
N° CAS	935666-88-9	Télécharger le SDF		Stockage des solutions mères	1 an-80°Cen solvant 1 mois-20°Cen solvant
Synonymes	N/A			Smiles	CC1=CC(=NN1)NC2=NC(=NC=C2Cl)NC(C)C3=NC=C(C=N3)F

Solubilité

In vitro
Lot:

DMSO : 70 mg/mL (200.7 mM)
(Le DMSO contaminé par lhumidité peut réduire la solubilité. Utiliser du DMSO frais et anhydre.)

Water : Insoluble

Ethanol : Insoluble

Calculateur de molarité

Masse	Concentration	Volume	Poids moléculaire
=	×	×

Calculateur de dilution Calculateur de poids moléculaire

In vivo Lot:
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	5%DMSO 1 40%PEG300 2 5%Tween80 3 50%ddH2O Validé par les laboratoires Selleck. Si vous avez besoin dajustements à cette formulation, contactez notre équipe de vente pour des tests personnalisés.	5.000mg/ml (14.34mM)	Taking the 1 mL working solution as an example, add 50 μL of 100 mg/ml clarified DMSO stock solution to 400 μL of PEG300, mix evenly to clarify it; add 50 μL of Tween80 to the above system, mix evenly to clarify; then continue to add 500 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.
Clear solution	5%DMSO 1 40%PEG300 2 5%Tween80 3 50%ddH2O Validé par les laboratoires Selleck. Si vous avez besoin dajustements à cette formulation, contactez notre équipe de vente pour des tests personnalisés.	5.000mg/ml (14.34mM)	Taking the 1 mL working solution as an example, add 50 μL of 100 mg/ml clarified DMSO stock solution to 400 μL of PEG300, mix evenly to clarify it; add 50 μL of Tween80 to the above system, mix evenly to make it clear; then continue to add 500 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.

Calculateur de formulation in vivo (Solution claire)

Étape 1 : Entrez les informations ci-dessous (Recommandé : Un animal supplémentaire pour tenir compte des pertes pendant lexpérience)

Dosage : mg/kg Poids moyen des animaux : g Volume de dosage par animal :μL Nombre danimaux :

Étape 2 : Entrez la formulation in vivo (Ceci nest que le calculateur, pas la formulation. Veuillez nous contacter dabord sil ny a pas de formulation in vivo dans la section Solubilité.)

% DMSO + % + % Tween 80 + % ddH₂O

%DMSO+ %

Résultats du calcul :

Concentration de travail : mg/ml;

Méthode de préparation du liquide maître DMSO : mg médicament prédissous dans μL DMSO ( Concentration du liquide maître mg/mL, Veuillez nous contacter dabord si la concentration dépasse la solubilité du DMSO du lot de médicament. )

Méthode de préparation de la formulation in vivo : Prendre μL DMSO liquide maître, ajouter ensuiteμL PEG300, mélanger et clarifier, ajouter ensuiteμL Tween 80, mélanger et clarifier, ajouter ensuite μL ddH₂O, mélanger et clarifier.

Méthode de préparation de la formulation in vivo : Prendre μL DMSO liquide maître, ajouter ensuite μL Huile de maïs, mélanger et clarifier.

Remarque : 1. Assurez-vous que le liquide est clair avant dajouter le solvant suivant.
2. Assurez-vous dajouter le(s) solvant(s) dans lordre. Vous devez vous assurer que la solution obtenue lors de lajout précédent est une solution claire avant de procéder à lajout du solvant suivant. Des méthodes physiques telles que le vortex, les ultrasons ou le bain-marie peuvent être utilisées pour faciliter la dissolution.

Mécanisme daction

Targets/IC₅₀/Ki	JAK2 (Cell-free assay) 0.26 nM
In vitro	Le 5μM AZD1480 induit un arrêt G2/M et la mort cellulaire en inhibant les kinases Aurora. Ce composé est un puissant inhibiteur de JAK2 qui peut supprimer la croissance, la survie, ainsi que la signalisation FGFR3 et STAT3 et les cibles en aval, y compris la Cycline D2, dans les cellules de myélome multiple humain. À de faibles concentrations micromolaires, il bloque la prolifération cellulaire et induit l'apoptose des lignées cellulaires de myélome. Ce produit chimique bloque efficacement la phosphorylation constitutive et induite par les stimuli de JAK1, JAK2 et STAT-3 dans les cellules de gliome humaines et murines, et entraîne une diminution de la prolifération cellulaire et l'induction de l'apoptose. C'est un inhibiteur puissant et compétitif à petite molécule de la kinase JAK1/2, et il est capable d'inhiber la phosphorylation de STAT3 et la croissance tumorale d'une manière dépendante de STAT3. Cet inhibiteur inhibe l'angiogenèse tumorale et les métastases en partie en affectant le microenvironnement tumoral.
Kinase Assay	essais kinase
Kinase Assay	Les études d'inhibition d'AZD1480 sont réalisées en utilisant les Jak1, Jak2 ou Jak3 recombinantes dans des conditions de tampon de 50 mM HEPES pH 7.3, 1 mM DTT, 0.01% Tween-20, 50 mM/ml BSA et 10 mM MgCl₂. L'enzyme Jak3 est exprimée sous forme de fusion GST N-terminale dans des cellules d'insectes et purifiée par chromatographies d'affinité au glutathion et d'exclusion de taille. Les enzymes sont testées en présence de ce composé (réponse dose-effet à 10 points, en triple, de 8.3 μM à 0.3 nM en étapes de dilution d'un demi-log) en utilisant 1.5 μM de substrat peptidique (Jak1: FITC-C6-KKHTDDGYMPMSPGVA-NH2, Jak2 et Jak3: FAM-SRCtide) et criblées sous leurs Km ATP respectifs (Jak1: 55 μM, Jak2: 15 μM, Jak3: 3 μM) et une concentration physiologique d'ATP approximative de 5 mM. Les peptides phosphorylés et non phosphorylés sont séparés et quantifiés par un système Caliper LC3000 pour le calcul du pourcentage d'inhibition.
In vivo	AZD1480 inhibe la phosphorylation de STAT3 dans un modèle de xénogreffe de tumeurs solides humaines et de myélome multiple. In vivo, ce composé inhibe la croissance des tumeurs sous-cutanées et augmente la survie des souris porteuses de tumeurs glioblastomateuses (GBM) intracrâniennes en inhibant l'activité de STAT-3, indiquant que l'inhibition pharmacologique de la voie JAK/STAT-3 par ce produit chimique devrait être envisagée pour une étude dans le traitement des patients atteints de tumeurs GBM. Il bloque l'infiltration pulmonaire des cellules myéloïdes et la formation de métastases pulmonaires dans les modèles expérimentaux syngéniques de souris et les modèles métastatiques spontanés. De plus, cet agent réduit l'angiogenèse et les métastases dans un modèle de xénogreffe de tumeur humaine. L'inhibiteur de Jak2 supprime la croissance des xénogreffes de tumeurs solides humaines hébergeant une activité Stat3 persistante.
Références	[1] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3255510/ [2] https://pubmed.ncbi.nlm.nih.gov/21164517/ [3] https://pubmed.ncbi.nlm.nih.gov/22027691/ [4] https://pubmed.ncbi.nlm.nih.gov/21920898/ [5] https://pubmed.ncbi.nlm.nih.gov/19962667/

Applications

Méthodes	Biomarqueurs	PMID
Western blot	p-STAT3 / STAT3 / p-JAK2 / JAK2 p-STAT1 / STAT1 / p-STAT5 / STAT5 / p-STAT6 / STAT6 p-ERK / ERK / p-p38 / p38 / SOCS3 / p-SHP2 / SHP2	22027691
Immunofluorescence	pSTAT5	30140255
Growth inhibition assay	Cell proliferation Cell viability	22027691

Informations sur lessai clinique

(données de https://clinicaltrials.gov, mis à jour le 2024-05-22)

Numéro NCT	Recrutement	Conditions	Sponsor/Collaborateurs	Date de début	Phases
NCT01219543	Terminated	Solid Tumour\|Advanced Solid Malignancies\|Child-Pugh A to B7 Advanced Hepatocellular Carcinoma\|EGFR and/or ROS Mutant NSCLC\|Lung Metastasis Carcinoma\|Gastric Cancer	AstraZeneca	November 2010	Phase 1
NCT01112397	Terminated	Solid Malignancies	AstraZeneca	April 2010	Phase 1

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