GSK-3 (Glycogen synthase kinase 3) is a serine/threonine protein kinase, consisting of GSK-3a and b subunit, which plays a key role in many different biological processes including tumorigenesis, cell survival, and developmental patterning. GSK-3 is constitutively active in non-stimulated cells and can negatively regulate canonical Wnt/b-catenin signaling[1]. AZD1080 is thiazole-derived inhibitor of GSK-3 with Ki values of 6.9 nM and 31 nM for GSK-3a and b, respectively, with >37-fold selectivity over CDKs. AZD1080 can inhibit tau phosphorylation through GSK3 in concentration-dependent manner, with IC50 value of 324 nM, in 3T3 fibroblasts engineered to stably express 4-repeat human tau. Similar effect of reduction on tau phosphorylation can also be observed in hippocampus of rats with acute oral administration of AZD1080 at 10 μmol/kg. Oral administration of AZD1080 at 15 μmol/kg can reverse MK-801-induced impairments in mouse model of cognition, as well as rescue LTP deficits in mouse hippocampal slices[2]. Treatment with AZD1080 on 1 - 4 μM can suppress cell proliferation, migration and invasion, as well as increase cell apoptosis and modulate NF-kB, Cyclin D1, MMP9, and P21 expression in endometrial cancer cells[3].
作用机制
AZD1080 binds in the ATP pocket of GSK3b where the oxindole ring system forms hydrogen bonds to the back-bone of the ATP pocket[2].
AZD1080 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Splenic T-cells
100, 10, 1, 0.1, 0.01 μg/mL
24 hours
To assess the impact of AZD1080 on splenic T-cell viability, results showed decreased viability at 100 μg/mL, but a slight increase in cell viability over the dose range 0.01 to 1 μg/mL.
Biomaterials. 2021 Feb;269:120635.
KPC cells
100, 10, 1, 0.1, 0.01 μg/mL
24 hours
To assess the impact of AZD1080 on KPC cell viability, results showed no significant changes.
Biomaterials. 2021 Feb;269:120635.
LLC cells
100, 10, 1, 0.1, 0.01 μg/mL
24 hours
To assess the impact of AZD1080 on LLC cell viability, results showed decreased viability at a high dose (100 μg/mL).
Biomaterials. 2021 Feb;269:120635.
CT26 cells
100, 10, 1, 0.1, 0.01 μg/mL
24 hours
To assess the impact of AZD1080 on CT26 cell viability, results showed slightly enhancing the viability at 10 and 100 μg/mL.
Biomaterials. 2021 Feb;269:120635.
MC38 cells
100, 10, 1, 0.1, 0.01 μg/mL
24 hours
To assess the impact of AZD1080 on MC38 cell viability, results showed that only the LLC cell line showed decreased viability at a high dose (100 μg/mL) of AZD1080, while slightly enhancing the viability of MC38 and CT26 cells at 10 and 100 μg/mL.
Biomaterials. 2021 Feb;269:120635.
OVCAR3
0.5 μM, 1.0 μM, 2.0 μM, 4.0 μM
Different time points
AZD1080 suppressed OVCAR3 cell proliferation in a concentration-dependent manner.
Drug Des Devel Ther. 2016 Mar 18;10:1225-32.
A2780
0.5 μM, 1.0 μM, 2.0 μM, 4.0 μM
Different time points
AZD1080 suppressed A2780 cell proliferation in a concentration-dependent manner.
Drug Des Devel Ther. 2016 Mar 18;10:1225-32.
AZD1080 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
MC38 colon cancer model
Intravenous injection
5 mg/kg
Every three days for a total of three times
To assess the therapeutic effect of AZD1080 on the MC38 colon cancer model, results showed that sAZD1080 significantly inhibited tumor growth, with 6 out of 15 mice becoming tumor-free.
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