product name AZD1080
Description: AZD1080 is a selective, orally bioactive, brain permeable GSK3 inhibitor, it inhibits human GSK3α and GSK3β with Ki of 6.9 nM and 31 nM, respectively, also it shows >14-fold selectivity against CDK2, CDK5, CDK1 and Erk2. AZD1080 has been reported to inhibit GSK3β by binding within the ATP pocket by means of the high resolution X-ray crystal structure. In addition, AZD1080 has been noted to suppression recombinant human GSK3α and GSK3β with the Ki values of 6.9 nM and 31 nM, respectively.
References: J Neurochem. 2013 May;125(3):446-56.
334.37
Formula
C19H18N4O2
CAS No.
612487-72-6
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)
DMSO: 52 mg/mL (155.5 mM)
Water: <1 mg/mL
Ethanol: <1 mg/mL
Solubility (In vivo)
30% PEG400+0.5% Tween80+5% propylene glycol: 20 mg/mL
Synonyms
other peoduct :References PubMed ID：:http://www.ncbi.nlm.nih.gov/pubmed/19423968
| In Vitro |
In vitro activity: 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. AZD1080 inhibits tau phosphorylation in cells expressing human tau, with IC50 of 324 nM. 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 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. |
|---|---|
| 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 |
| Animal model | C57BL/6 mice |
| Formulation & Dosage | Dissolved in water with 0.5% ascorbic acid, 0.01% EDTA, pH 2.0; 3 or 10 μmol/kg, 6 mL/kg; Oral gavage |
| References | J Neurochem. 2013 May;125(3):446-56. |
