Glycogen synthase kinase 3 (GSK3) is a serine/threonine kinase involved in the pathogenesis of diabetes and Alzheimer's disease. AR-A014418 is a GSK3 inhibitor with an IC50 value of 104±27nM. It inhibits GSK3 in an ATP-competitive manner (Ki=38nM). In 3T3 fibroblasts stably expressing four-repeat tau protein, AR-A014418 (100nM-50μM) inhibited tau phosphorylation in a dose-dependent manner with an IC50 of 2.7μM. AR-A014418 also protected neuroblastoma N2A cells from death induced by reduced PI3K pathway activity in a dose-dependent manner with an IC50 of 0.5μM[3]. Intraperitoneal injection of JNJ-63533054 (1-4μg/g) dose-dependently delayed the onset of symptoms, slowed down disease progression, and inhibited the activity of GSK-3 in an amyotrophic lateral sclerosis mouse model harboring the G93A mutant human SOD1 gene[4].
作用机制
AR-A014418 is a thiazole that inhibits GSK3 in an ATP-competitive manner[3].
AR-A014418 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Hippocampal neurons
10 µM
1 hour
AR-A014418 significantly inhibited AMPA-induced GluR1 receptor internalization by 48%.
Proc Natl Acad Sci U S A. 2010 Jun 22;107(25):11573-8.
A375
20 µM
12 hours
To detect the effect of AR-A014418 on PD-L1 expression, it was found that AR-A014418 inhibited PD-L1 expression.
J Immunother Cancer. 2023 May;11(5):e006483.
Hela
40 µM
16 hours
To detect the effect of AR-A014418 on PD-L1 expression, it was found that AR-A014418 inhibited PD-L1 expression.
J Immunother Cancer. 2023 May;11(5):e006483.
IEC-6 cells
10 µM
24 hours
To investigate the effect of AR-A014418 on the migration of IEC-6 cells, results showed that AR-A014418 inhibited cell migration under all conditions.
Cell Mol Life Sci. 2006 Dec;63(23):2871-9.
NRCMs
1 µM
24 hours
To study the function of eEF2K in DIC, it was found that eEF2K overexpression alleviated DOX-induced cardiomyocyte injury and atrophy
Cell Biol Toxicol. 2024 Dec 21;41(1):15.
22Rv1
0.25 µM
30 hours
AR-A014418 activates AR in the absence of androgens, increasing AR reporter gene activity.
2008 Jun;10(6):624-34. doi: 10.1593/neo.08248.
PC3
0.5 µM
4 hours
AR-A014418 stimulates nuclear translocation of AR in the absence of androgens.
2008 Jun;10(6):624-34. doi: 10.1593/neo.08248.
LUHMES cells
2 µM
6 hours
To measure the effect of GSK-3 inhibitors on tau phosphorylation, results showed that AR-A014418 at 2 µM did not significantly reduce tau phosphorylation levels.
Br J Pharmacol. 2007 Nov;152(6):959-79.
LNCaP
0.25 µM
96 hours
AR-A014418 stimulates the proliferation of LNCaP cells in the absence of androgens.
2008 Jun;10(6):624-34. doi: 10.1593/neo.08248.
Primary cultured neurons
33 µM
Inhibition of GSK-3β significantly reduced the levels of full-length fractalkine in total cell extracts, mainly affecting the plasma membrane-associated form of the protein.
Cell Mol Life Sci. 2017 Mar;74(6):1153-1163.
HEK293 cells
33 µM
GSK-3β inhibition led to decreased levels of fractalkine at the plasma membrane, which in turn reduced the levels of soluble fractalkine.
Cell Mol Life Sci. 2017 Mar;74(6):1153-1163.
AR-A014418 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
Seipin-nKO mice
Intraperitoneal injection
1 mg/kg
Once daily for 28 days
AR-A014418 treatment partially reduced the level of cleaved caspase-3 and alleviated the deficits in motor coordination.
Cell Death Dis. 2018 May 1;9(5):440
C57BL/6 mice
5-HT2A receptor function model
Intraperitoneal injection
10 or 20 mg/kg
Single administration
To test the effect of AR-A014418 on DOI-induced head-twitch response (HTR) and ear-scratch response (ESR). Results showed that AR-A014418 did not significantly affect the DOI-induced HTR or ESR.
Br J Pharmacol. 2018 Jul;175(13):2599-2610
C57BL/6 mice
Acute DIC model
Intraperitoneal injection
15 mg/kg
Single injection, lasting 5 days
To study the role of eEF2K in DIC, it was found that eEF2K overexpression alleviated DOX-induced cardiac dysfunction and myocardial mass loss
Cell Biol Toxicol. 2024 Dec 21;41(1):15.
Rabbit
Preterm rabbit model of intraventricular hemorrhage
Intramuscular injection
20 mg/kg
Twice a day for seven days
GSK-3 β inhibition accelerated OPC maturation, myelination, and neurological recovery, and reduced microglia infiltration and IL1 β expression
Neurobiol Dis. 2018 Oct;118:22-39
Rats
12-day old postnatal rat model
Oral
30 mg/kg
Single dose, duration of 2, 4, 6 hours
To evaluate the effect of AR-A014418 on tau phosphorylation in vivo, results showed that AR-A014418 did not significantly reduce tau phosphorylation levels in the cortex or hippocampus at any time point.
Br J Pharmacol. 2007 Nov;152(6):959-79.
Mice
Tail suspension test and forced swim test
30 μmol/kg
14 days
AR-A014418 enhanced surface GluR1 levels in the hippocampal region and showed antidepressant-like effects in the tail suspension and forced swim tests.
Proc Natl Acad Sci U S A. 2010 Jun 22;107(25):11573-8.
Rats
Hindlimb suspension model
Intraperitoneal injection
4 mg/kg
Once daily for 7 days
To investigate the effect of AR-A014418 on ribosome biogenesis and protein synthesis rates in rat soleus muscle under hindlimb suspension conditions. Results showed that AR-A014418 partially attenuated the unloading-induced decline in markers of ribosome biogenesis and protein synthesis rates.
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