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,with IC50 of 324 nM, inhibits tau phosphorylation in cells expressing human tau. 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.
|Source||Oncotarget (2016). Figure 10. AZD1080|
|Method||cell proliferation assay|
|Cell Lines||EC cell|
|Concentrations||1.0, 2.0, 4.0 μM|
|Incubation Time||0 h, 24 h, 48 h, and 72 h|
|Results||The MTT assay showed a significant reduction of cell viability started from 0.5 μM when exposed to AZD1080 compared with the DMSO group, and thus the www.impactjournals.com/oncotarget 27546 Oncotarget concentration of 1.0, 2.0, 4.0μM was used for further study|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO 40 mg/mL|
AZD1080, a novel GSK3 inhibitor, rescues synaptic plasticity deficits in rodent brain and exhibits peripheral target engagement in humans.
Georgievska B,et al. J Neurochem. 2013 May;125(3):446-56. PMID: 23410232.
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SB415286 is a potent GSK3α inhibitor with IC50/Ki of 78 nM/31 nM with equally effective inhibition of GSK-3β.
TDZD-8 is a non-ATP competitive GSK-3β inhibitor with IC50 of 2 μM; minimal inhibitory effect observed on CDK1, casein kinase II, PKA and PKC.
LY2090314 is a potent GSK-3 inhibitor for GSK-3α/β with IC50 of 1.5 nM/0.9 nM; may improve the efficacy of platinum-based chemotherapy regimens. Phase 1/2.
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