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AZD1080

Name: AZD1080
Brand: Selleck Chemicals
SKU: S7145
Rating: 5 (6 reviews)

Catalog No.S7145

For research use only.

AZD1080 is a selective, orally active, brain permeable GSK3 inhibitor, inhibits human GSK3α and GSK3β with K_i of 6.9 nM and 31 nM, respectively, shows >14-fold selectivity against CDK2, CDK5, CDK1 and Erk2.

CAS No. 612487-72-6

Selleck's AZD1080 has been cited by 6 Publications

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GSK-3 Signaling Pathway Map

Biological Activity

Description

Features

A brain permeable GSK3 inhibitor.

Targets

GSK-3α ^[1] (Cell-free assay)	GSK-3β ^[1] (Cell-free assay)
6.9 nM	31 nM

In vitro

AZD1080 is a selective, orally active, brain permeable GSK3 inhibitor, inhibits human GSK3α and GSK3β with a K_i of 6.9 nM and 31 nM, respectively, shows >14-fold selectivity against cdk2, cdk5, cdk1 and Erk2. AZD1080 inhibits tau phosphorylation in cells expressing human tau, with IC50 of 324 nM. ^[1]

In vivo

AZD1080 inhibits tau phosphorylation in rat brain after oral dministration, with brain/plasma exposure ratio of 0.5 – 0.8 at peak concentrations. AZD1080 reverses cognitive deficits and rescues dysfunctional synapses in mice. Acute oral treatment with AZD1080 inhibits peripheral GSK3 activity, produces a dose-dependent reduction of the phosphorylated to total glycogen synthase (GS) ratio, with a mean maximal inhibitory effect of 49% at the highest dose (10 μmol/kg) at 2 h after dosing. ^[1]

Protocol (from reference)

Kinase Assay:^[1]	Kinase Assay: GSK3 scintillation proximity assay is done. The competition experiments are carried out in duplicate with 10 concentrations of the inhibitor in clear-bottomed microtiter plates. The biotinylated peptide substrate biotin-AAEELDSRAGS(PO3H2)PQL, is added at a final concentration of 2 μM in an assay buffer containing 6 milliunits of recombinant human GSK3 (equal mix of both α and β), 12 mM MOPS, pH 7.0, 0.3 mM EDTA, 0.01% β-mercaptoethanol, 0.004% Brij 35, 0.5% glycerol, and 0.5 μg of bovine serum albumin/25 μl and preincubated for 10–15 min. The reaction is initiated by the addition of 0.04 μCi of [γ-³³P]ATP and unlabeled ATP in 50 mM Mg(Ac)₂ to a final concentration of 1 μM ATP and assay volume of 25 μl. Blank controls without peptide substrate are used. After incubation for 20 min at room temperature, each reaction is terminated by the addition of 25 μl of stop solution containing 5 mM EDTA, 50 μM ATP, 0.1% Triton X-100, and 0.25 mg of streptavidin-coated SPA beads corresponding to 35 pmol of binding capacity. After 6 h the radioactivity is determined in a liquid scintillation counter.
Cell Research:^[1]	Cell lines: 3T3 fibroblasts stably expressing 4-repeat human tau Concentrations: ~20mM Incubation Time: 0-8 h Method: 3T3 fibroblasts are engineered to stably express four-repeat tau protein. These cells have high endogenous levels of GSK3 that is able to phosphorylate tau protein constitutively. This phosphorylation is inhibited by LiCl. After treatment with different compounds, cultures are washed twice with 5 mM MgCl₂-PBS. Extracts for Western blot analysis are prepared by homogenizing cells in ice-cold extraction buffer consisting of 20 mM HEPES, pH 7.4, 100 mM NaCl, 10 mM NaF, 1% Triton X-100, 1 mM sodium orthovanadate, 10 mM EDTA, and protease inhibitors (2 mM phenylmethylsulfonyl fluoride, 10 μg/ml aprotinin, 10 μg/ml leupeptin, and 10 μg/ml pepstatin). The samples are homogenized at 4 °C, and protein content is determined by Bradford method. Total protein (25 μg) is electrophoresed on 10% SDS-PAGE gel and transferred to a nitrocellulose membrane. The experiments are performed using the following primary antibodies: tau Ser(P)-396, 1:1000; Tau5, 1:1000; and anti-GSK3β, 1:1000. The filters are incubated with the antibody at 4 °C overnight in 5% nonfat dried milk. A secondary antibody (1:5000), followed by ECL detection reagents are used for immunodetection. Quantitation of immunoreactivity is performed by densitometric scanning.
Animal Research:^[1]	Animal Models: C57BL/6 mice Dosages: 3 or 10 μmol/kg, 6 mL/kg Administration: oral gavage

References

[1] Georgievska B, et al. J Neurochem, 2013, 125(3), 446-456.

Solubility (25°C)

In vitro


In vivo	Add solvents to the product individually and in order (Data is from Selleck tests instead of citations): 30% PEG400+0.5% Tween80+5% propylene glycol For best results, use promptly after mixing. Click to purchase: PEG400 Tween 80	20 mg/mL (suspension)

Chemical Information

Molecular Weight	334.37
Formula	C₁₉H₁₈N₄O₂
CAS No.	612487-72-6
Storage	3 years	-20°C	powder
Storage	2 years	-80°C	in solvent
Smiles	C1COCCN1CC2=CN=C(C=C2)C3=C(NC4=C3C=C(C=C4)C#N)O

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Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

Handling Instructions

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