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AZD1480 JAK remmer

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

Cat.Nr.S2162

AZD1480 is een nieuwe ATP-competitieve JAK2-remmer met een IC50 van 0,26 nM in een celvrije test, selectiviteit tegen JAK3 en Tyk2, en in mindere mate tegen JAK1. Fase 1.

Chemische structuur

Moleculair gewicht: 348.77

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Kwaliteitscontrole

Batch: Zuiverheid: 99.16%

99.16

Gerelateerde doelwitten	EGFR STAT Pim
Overige JAK Inhibitoren	BMS-986165 (Deucravacitinib) WP1066 Momelotinib (CYT387) Filgotinib (GLPG0634) AT9283 Gandotinib (LY2784544) Pacritinib TG101209 Cerdulatinib (PRT062070) hydrochloride NVP-BSK805 2HCl

Celkweek, behandeling & werkconcentratie

Cellijnen	Assaytype	Concentratie	Incubatietijd	Formulering	Activiteitsbeschrijving	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
Klik om meer experimentele gegevens over de cellijn te bekijken

Chemische informatie, Opslag en Stabiliteit

Moleculair gewicht	348.77	Formule	C₁₄H₁₄ClFN₈	Opslag (Vanaf de ontvangstdatum)	3 jaar-20°Cpoeder
CAS-nr.	935666-88-9	SDF downloaden		Opslag van stamoplossingen	1 jaar-80°Cin oplosmiddel 1 maand-20°Cin oplosmiddel
Synoniemen	N/A			Smiles	CC1=CC(=NN1)NC2=NC(=NC=C2Cl)NC(C)C3=NC=C(C=N3)F

Oplosbaarheid

In vitro
Batch:

DMSO : 70 mg/mL (200.7 mM)
(Met vocht verontreinigde DMSO kan de oplosbaarheid verminderen. Gebruik verse, watervrije DMSO.)

Water : Insoluble

Ethanol : 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.
Clear solution	5%DMSO 1 40%PEG300 2 5%Tween80 3 50%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 (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 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 (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.

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

Targets/IC₅₀/Ki	JAK2 (Cell-free assay) 0.26 nM
In vitro	5μM AZD1480 veroorzaakt G2/M-arrest en celdood door Aurora-kinasen te remmen. Deze verbinding is een krachtige JAK2-remmer die groei, overleving, evenals FGFR3- en STAT3-signalering en stroomafwaartse doelwitten, waaronder Cyclin D2, in menselijke multipel myeloomcellen kan onderdrukken. Bij lage micromolaire concentraties blokkeert het celproliferatie en induceert het apoptose van myeloomcellijnen. Deze chemische stof blokkeert effectief constitutieve en stimulus-geïnduceerde JAK1-, JAK2- en STAT-3-fosforylering in zowel menselijke als muizenglioomcellen, en leidt tot een afname van celproliferatie en inductie van apoptose. Het is een krachtige, competitieve kleine-molecule-remmer van JAK1/2-kinase, en het is in staat om STAT3-fosforylering en tumorgroei op een STAT3-afhankelijke manier te remmen. Deze remmer remt tumorangiogenese en metastase gedeeltelijk door het tumormicroklimaat te beïnvloeden.
Kinase Assay	kinase testen
Kinase Assay	Inhibitiestudies van AZD1480 worden uitgevoerd met recombinante Jak1, Jak2 of Jak3 onder buffervoorwaarden van 50 mM HEPES pH 7.3, 1 mM DTT, 0.01% Tween-20, 50 mM/ml BSA en 10 mM MgCl₂. Het Jak3-enzym wordt tot expressie gebracht als N-terminale GST-fusie in insectencellen en gezuiverd door glutathion-affiniteits- en grootte-exclusiechromatografieën. Enzymen worden getest in aanwezigheid van deze verbinding (10-punts dosisrespons, in drievoud, van 8.3 μM tot 0.3 nM in half-log verdunningsstappen) met behulp van 1.5 μM peptidesubstraat (Jak1: FITC-C6-KKHTDDGYMPMSPGVA-NH2, Jak2 en Jak3: FAM-SRCtide) en gescreend onder hun respectievelijke ATP Km (Jak1: 55 μM, Jak2: 15 μM, Jak3: 3 μM) en benaderde fysiologische ATP-concentratie van 5 mM. Gefosforyleerde en niet-gefosforyleerde peptiden worden gescheiden en gekwantificeerd door een Caliper LC3000-systeem voor het berekenen van het percentage remming.
In vivo	AZD1480 remt de STAT3-fosforylering in een xenograftmodel van humane solide tumoren en multipel myeloom. In vivo remt deze verbinding de groei van subcutane tumoren en verhoogt het de overleving van muizen met intracraniale glioblastoma (GBM)-tumoren door de STAT-3-activiteit te remmen, wat aangeeft dat farmacologische remming van de JAK/STAT-3-route door deze chemische stof overwogen moet worden voor onderzoek naar de behandeling van patiënten met GBM-tumoren. Het blokkeert longinfiltratie van myeloïde cellen en de vorming van longmetastasen in zowel muis-syngene experimentele als spontane metastatische modellen. Bovendien vermindert dit middel angiogenese en metastase in een humaan xenografttumormodel. De Jak2-remmer onderdrukt de groei van humane solide tumoren xenografts met aanhoudende Stat3-activiteit.
Referenties	[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/

Toepassingen

Methoden	Biomarkers	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

Informatie klinische proef

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

NCT-nummer	Rekrutering	Aandoeningen	Sponsor/Medewerkers	Startdatum	Fasen
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

Technische ondersteuning

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