Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase involved in cell differentiation, cellular growth and proliferation, apoptosis, and inflammation. There are two isoforms of GSK-3, GSK-3α and GSK-3β. 1-Azakenpaullone is a potent inhibitor of GSK-3β with an IC50 value of 18 nM. In contrast, the IC50 values of 1-Azakenpaullone against CDK1/cycline B and CDK5/p25 were 2.0 and 4.2 μM, respectively[3]. 1-Azakenpaullone at the concentrations of 5, 10, and 15 μM significantly promoted DNA synthesis in human pancreatic islets above the levels at 8 mM glucose. Exposure of human pancreatic islets to 8 mM glucose and 15 μM 1-Azakenpaullone significantly reduced cells in G0/G1 phase and increased cells in S phase. Combined treatment of human islets with 8 mM glucose and 5 μM 1-Azakenpaullone significantly increased Ki-67+/insulin+ cells as compared with basal glucose[4]. After 2-week administration of 1-Azakenpaullone, a significant reduction in the levels of phosphorylated Akt GSK-3β, and cyclin D1 was observed in the islets of c-KitW/+ mice when compared to c-Kit+/+ mice[5].
1-Azakenpaullone 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Human fetal cortical neurons
50, 100, 400 nM
2-4 days
Enhanced KCC2 mRNA and protein expression
Nat Commun. 2021 Oct 27;12(1):6208.
Embryonic chick atrial myocytes
2-5 µM
24 hours
To investigate the inhibitory effect of Kenpaullone on GSK3β and its impact on SREBP-1 and GIRK4 expression. Results showed that Kenpaullone dose-dependently increased the expression of nSREBP-1 and GIRK4.
Diabetes. 2014 Jun;63(6):2097-113.
Islet cells
10 µM
24 hours
To evaluate the effect of 1-AKP on insulin secretion in islet cells. Results showed that islets from 1-AKP-treated c-KitWv/+ mice exhibited a significant increase in insulin secretion in response to 22 mM glucose, with a 2-fold increase compared to the untreated group.
Lab Invest. 2012 Apr;92(4):543-55.
HEK 293T cells
5 µM
24 hours
To investigate the effect of ubiquitination on PXR protein levels, results showed that MG-132 effectively stabilized PXR protein.
Cells. 2022 Jan 13;11(2):264.
HepG2 cells
5 µM
24 hours
To investigate the effect of CDK inhibitors on PXR protein levels, results showed that kenpaullone significantly increased PXR protein levels.
Cells. 2022 Jan 13;11(2):264.
RAW 264.7 macrophages
150 nM
24 hours
To investigate the effect of 1-Azakenpaullone on RANKL-induced NFATc1 nucleotranslocation, results showed that 1-Azakenpaullone significantly reversed the inhibitory effects of fucoidan on NFATc1 phosphorylation and nucleotranslocation.
Mar Drugs. 2019 Jun 10;17(6):345.
Primary cortical neurons
0.25–2 µM
36 hours
KEN enhanced ADAM10 protein levels
Adv Sci (Weinh). 2024 Mar;11(11):e2305260.
HT22 cells
0.25–2 µM
36 hours
KEN enhanced ADAM10 protein levels
Adv Sci (Weinh). 2024 Mar;11(11):e2305260.
HEK293 cells
0.25–2 µM
36 hours
KEN enhanced ADAM10 protein levels
Adv Sci (Weinh). 2024 Mar;11(11):e2305260.
Rat primary cortical neurons
0.1 µM, 0.2 µM, 0.5 µM
3 days
Enhanced Kcc2 mRNA expression in a dose-dependent manner
Nat Commun. 2021 Oct 27;12(1):6208.
SH-SY5Y cells
0.25–2 µM
36 hours
KEN significantly increased m-ADAM10 protein levels
Adv Sci (Weinh). 2024 Mar;11(11):e2305260.
Rat islet cells
5, 10, 15 µM
4 days
To assess DNA synthesis and cell cycle progression. Results showed that 1-Akp significantly increased DNA synthesis, which was sensitive to rapamycin.
Diabetes. 2009 Mar;58(3):663-72.
Human islet cells
5, 10, 15 µM
4 days
To assess DNA synthesis, cell cycle progression, and β-cell proliferation. Results showed that 1-Akp significantly enhanced DNA synthesis, which was sensitive to rapamycin.
Diabetes. 2009 Mar;58(3):663-72.
Adult human skin fibroblasts
1 µM
starting at 14 dpi
Kenpaullone significantly promotes the survival of ALS-hiMNs, enhances dendritic outgrowth and branching, rescues soma size, completely normalizes excitability, and restores the ability to form NMJs and control muscle activity.
Cell Rep. 2016 Jan 5;14(1):115-128.
1-Azakenpaullone 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
Nerve constriction injury pain model and bone cancer pain model
Intraperitoneal and intrathecal injection
10-30 mg/kg
Daily injections for 7-14 days
KP significantly alleviated neuropathic pain and bone cancer pain, and repaired Kcc2 expression deficits in the spinal cord dorsal horn
Nat Commun. 2021 Oct 27;12(1):6208.
Mice
C-KitWv/+ male mice
Intraperitoneal injection
2mg/kg
Every other day for 2 weeks
To evaluate the effect of 1-AKP on glucose metabolism and β-cell function in c-KitWv/+ mice. Results showed that 1-AKP treatment significantly improved fasting blood glucose levels, glucose tolerance, and insulin secretion, and increased β-cell mass and proliferation in c-KitWv/+ mice.
Lab Invest. 2012 Apr;92(4):543-55.
Zebrafish
Zebrafish lateral-line neuromasts
Immersion
30–50 µM
20 hours
Evaluating the protective effect of kenpaullone against cisplatin-induced hair cell loss in zebrafish lateral-line neuromasts, results showed kenpaullone significantly reduced hair cell loss.
J Exp Med. 2018 Apr 2;215(4):1187-1203.
FVB mice
Cisplatin-induced ototoxicity model
Transtympanic injection
50 μM
1 hour before and 24 hours after cisplatin administration
Evaluated the protective effect of 1-Azakenpaullone against cisplatin-induced ototoxicity, showing significant reduction in hearing loss.
J Med Chem. 2018 Sep 13;61(17):7700-7709.
APP/PS1 mice
Alzheimer's disease model
Intraperitoneal injection
7 mg/kg
Every other day for 2 months
KEN promoted ADAM10 expression and improved cognitive functions
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