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AZD1480 JAK inibitore

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

N. Cat.S2162

AZD1480 è un nuovo inibitore di JAK2 competitivo dell'ATP con un'IC50 di 0,26 nM in un saggio senza cellule, selettività contro JAK3 e Tyk2 e in misura minore contro JAK1. Fase 1.

AZD1480 JAK inibitore Chemical Structure

Struttura chimica

Peso molecolare: 348.77

Vai a

Controllo Qualità

Lotto: Purezza: 99.16%

99.16

Target correlati	EGFR STAT Pim
Altro JAK Inibitori	BMS-986165 (Deucravacitinib) WP1066 Momelotinib (CYT387) Filgotinib (GLPG0634) AT9283 Gandotinib (LY2784544) Pacritinib TG101209 Cerdulatinib (PRT062070) hydrochloride NVP-BSK805 2HCl

Coltura cellulare, trattamento e concentrazione di lavoro

Linee cellulari	Tipo di saggio	Concentrazione	Tempo di incubazione	Formulazione	Descrizione dellattività	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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Informazioni chimiche, conservazione e stabilità

Peso molecolare	348.77	Formula	C₁₄H₁₄ClFN₈	Conservazione (Dalla data di ricezione)	3 anni-20°Cpolvere
N. CAS	935666-88-9	Scarica SDF		Conservazione delle soluzioni stock	1 anno-80°Cin solvente 1 mese-20°Cin solvente
Sinonimi	N/A			Smiles	CC1=CC(=NN1)NC2=NC(=NC=C2Cl)NC(C)C3=NC=C(C=N3)F

Solubilità

In vitro
Lotto:

DMSO : 70 mg/mL (200.7 mM)
(Il DMSO contaminato da umidità può ridurre la solubilità. Utilizzare DMSO fresco e anidro.)

Water : Insoluble

Ethanol : Insoluble

Calcolatore di Molarità

Massa	Concentrazione	Volume	Peso molecolare
=	×	×

Calcolatore di Diluizione Calcolatore del Peso Molecolare

In vivo Lotto:
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 Validato dai laboratori Selleck. Se necessiti di modifiche a questa formulazione, contatta il nostro team di vendita per test personalizzati.	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 Validato dai laboratori Selleck. Se necessiti di modifiche a questa formulazione, contatta il nostro team di vendita per test personalizzati.	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.

Calcolatore di formulazione in vivo (Soluzione chiara)

Passo 1: Inserire le informazioni di seguito (Consigliato: Un animale aggiuntivo per tenere conto della perdita durante lesperimento)

Dosaggio: mg/kg Peso medio degli animali: g Volume di dosaggio per animale:μL Numero di animali:

Passo 2: Inserire la formulazione in vivo (Questo è solo il calcolatore, non la formulazione. Contattateci prima se non cè una formulazione in vivo nella sezione Solubilità.)

% DMSO + % + % Tween 80 + % ddH₂O

%DMSO+ %

Risultati del calcolo:

Concentrazione di lavoro: mg/ml;

Metodo per preparare il liquido master di DMSO: mg farmaco predissolto in μL DMSO ( Concentrazione del liquido master mg/mL, Vi preghiamo di contattarci prima se la concentrazione supera la solubilità del DMSO del lotto del farmaco. )

Metodo per preparare la formulazione in vivo: Prendere μL DMSO liquido master, quindi aggiungereμL PEG300, mescolare e chiarire, quindi aggiungereμL Tween 80, mescolare e chiarire, quindi aggiungere μL ddH₂O, mescolare e chiarire.

Metodo per preparare la formulazione in vivo: Prendere μL DMSO liquido master, quindi aggiungere μL Olio di mais, mescolare e chiarire.

Nota: 1. Si prega di assicurarsi che il liquido sia limpido prima di aggiungere il solvente successivo.
2. Assicurarsi di aggiungere il/i solvente/i in ordine. È necessario assicurarsi che la soluzione ottenuta, nellaggiunta precedente, sia una soluzione limpida prima di procedere allaggiunta del solvente successivo. Metodi fisici come il vortex, gli ultrasuoni o il bagno dacqua calda possono essere utilizzati per facilitare la dissoluzione.

Meccanismo dazione

Targets/IC₅₀/Ki	JAK2 (Cell-free assay) 0.26 nM
In vitro	5μM AZD1480 induce l'arresto G2/M e la morte cellulare inibendo le chinasi Aurora. Questo composto è un potente inibitore di JAK2 in grado di sopprimere la crescita, la sopravvivenza, nonché la segnalazione di FGFR3 e STAT3 e i bersagli a valle, inclusa la Ciclina D2 nelle cellule di mieloma multiplo umano. A basse concentrazioni micromolari, blocca la proliferazione cellulare e induce l'apoptosi delle linee cellulari del mieloma. Questa sostanza chimica blocca efficacemente la fosforilazione costitutiva e indotta da stimoli di JAK1, JAK2 e STAT-3 sia nelle cellule di glioma umane che murine, e porta a una diminuzione della proliferazione cellulare e all'induzione dell'apoptosi. È un potente inibitore competitivo a piccola molecola della chinasi JAK1/2 ed è in grado di inibire la fosforilazione di STAT3 e la crescita tumorale in modo dipendente da STAT3. Questo inibitore inibisce l'angiogenesi e la metastasi tumorale in parte influenzando il microambiente tumorale.
Saggio chinasico	saggi chinasici
Saggio chinasico	Gli studi di inibizione di AZD1480 sono condotti utilizzando Jak1, Jak2 o Jak3 ricombinanti in condizioni di tampone di 50 mM HEPES pH 7,3, 1 mM DTT, 0,01% Tween-20, 50 mM/ml BSA e 10 mM MgCl₂. L'enzima Jak3 è espresso come fusione GST N-terminale in cellule di insetto e purificato mediante cromatografie di affinità al glutatione e di esclusione dimensionale. Gli enzimi sono saggiati in presenza di questo composto (risposta dose di 10 punti, in triplicato, da 8,3 μM a 0,3 nM in passaggi di diluizione a metà log) utilizzando 1,5 μM di substrato peptidico (Jak1: FITC-C6-KKHTDDGYMPMSPGVA-NH2, Jak2 e Jak3: FAM-SRCtide) e schermati sotto i loro rispettivi ATP Km (Jak1: 55 μM, Jak2: 15 μM, Jak3: 3 μM) e una concentrazione fisiologica approssimativa di ATP di 5 mM. I peptidi fosforilati e non fosforilati vengono separati e quantificati da un sistema Caliper LC3000 per il calcolo della percentuale di inibizione.
In vivo	AZD1480 inibisce la fosforilazione di STAT3 in un modello di xenotrapianto di tumori solidi umani e mieloma multiplo. In vivo, questo composto inibisce la crescita dei tumori sottocutanei e aumenta la sopravvivenza dei topi portatori di tumori di glioblastoma intracranico (GBM) inibendo l'attività di STAT-3, indicando che l'inibizione farmacologica della via JAK/STAT-3 da parte di questo agente chimico dovrebbe essere considerata per lo studio nel trattamento dei pazienti con tumori GBM. Blocca l'infiltrazione polmonare delle cellule mieloidi e la formazione di metastasi polmonari sia in modelli sperimentali singenici di topo che in modelli metastatici spontanei. Inoltre, questo agente riduce l'angiogenesi e le metastasi in un modello di tumore xenotrapiantato umano. L'inibitore di Jak2 sopprime la crescita di xenotrapianti di tumori solidi umani che ospitano attività Stat3 persistente.
Riferimenti	[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/

Applicazioni

Metodi	Biomarcatori	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

Informazioni sullo studio clinico

(dati da https://clinicaltrials.gov, aggiornato il 2024-05-22)

Numero NCT	Reclutamento	Condizioni	Sponsor/Collaboratori	Data di inizio	Fasi
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

Supporto tecnico

Istruzioni per la manipolazione

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