Home PI3K/Akt/mTOR GSK-3 inhibitor AZD1080

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AZD1080 GSK-3 inhibitor

Cat.No.S7145

AZD1080 is a selective, orally active, brain permeable GSK3 inhibitor, inhibits human GSK3α and GSK3β with Ki of 6.9 nM and 31 nM, respectively, shows >14-fold selectivity against CDK2, CDK5, CDK1 and Erk2.
AZD1080 GSK-3 inhibitor Chemical Structure

Chemical Structure

Molecular Weight: 334.37

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Quality Control

Batch: Purity: 99.97%
99.97

Solubility

In vitro
Batch:

DMSO : 52 mg/mL (155.51 mM)
(Moisture-contaminated DMSO may reduce solubility. Use fresh, anhydrous DMSO.)

Water : Insoluble

Ethanol : Insoluble

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In vivo
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Method for preparing in vivo formulation: Take μL DMSO master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O, mix and clarify.

Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.

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Chemical Information, Storage & Stability

Molecular Weight 334.37 Formula

C19H18N4O2

 Storage (From the date of receipt)
CAS No. 612487-72-6 Download SDF Storage of Stock Solutions

Synonyms N/A Smiles C1COCCN1CC2=CN=C(C=C2)C3=C(NC4=C3C=C(C=C4)C#N)O

Mechanism of Action

Features
A brain permeable GSK3 inhibitor.
Targets/IC50/Ki
GSK-3α
(Cell-free assay)
6.9 nM
GSK-3β
(Cell-free assay)
31 nM
In vitro

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

Kinase Assay
Kinase Assay
GSK3 scintillation proximity assay is done. The competition experiments are carried out in duplicate with 10 concentrations of this compound 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.
In vivo

AZD1080 inhibits tau phosphorylation in rat brain after oral administration, with brain/plasma exposure ratio of 0.5 – 0.8 at peak concentrations. This compound reverses cognitive deficits and rescues dysfunctional synapses in mice. Acute oral treatment with this chemical 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.

References

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