NUAK family SNF1-like kinase-1 (NUAK1) and NUAK2 are the members of the AMPK family that play important roles in regulating essential cellular events, such as cell invasion, proliferation, embryonic development and axon branching. WZ4003 is an inhibitor of both NUAK isoforms with IC50 values of 20 nM and 100 nM for NUAK1 and NUAK2, respectively. In HEK-293 cells, EDTA-induced phosphorylation of MYPT1 at Ser445 was suppressed by WZ4003 (0.3 - 10 mM) in a dose-dependent manner. In HEK-293 cells expressing drug-resistant NUAK1[A195T], WZ4003 at 30 μM failed to block the phosphorylation of MYPT1. However, WZ4003 at 3 - 10 μM effectively suppressed MYPT1 Ser445 phosphorylation. Treatment with 10 μM WZ4003 remarkably reduced cell migration in wild-type mouse embryonic fibroblasts (MEFs). In both U2OS cells and MEFs, WZ4003 at 10 μM suppressed cell proliferation and MYPT1 phosphorylation to the same level as shown in NUAK1 knockout cells. The invasion potential of U2OS cells was also inhibited by 10 μM WZ4003[3]. In the Ba/F3 cell line, the IC50 values of WZ4003 against L858R/T790M mutant and T790M mutant were 1.90 mM and 1.29 mM, respectively[4].
WZ4003 细胞实验
Cell Line
Concentration
Treated Time
Description
References
U2OS cells
10 µM
1000 minutes
WZ4003 markedly restricted cells from entering mitosis, similar to the effect of the RO3306 CDK1 inhibitor.
Biochem J. 2014 Jul 15;461(2):233-45.
HEK-293 cells
3–10 µM
16 hours
To evaluate the inhibitory effect of WZ4003 on NUAK1 activity, results showed that WZ4003 significantly inhibited MYPT1 Ser445 phosphorylation at concentrations of 3–10 μM.
Biochem J. 2014 Jan 1;457(1):215-25.
Human jaw bone marrow mesenchymal stem cells
5 µM
2 hours
Suppress the APN-induced overexpression of CXCL1 and CXCL8
J Cell Mol Med. 2017 Jul;21(7):1411-1419.
Human brain slice cultures (HBSCs)
10 µM
2 weeks
To assess the impact of WZ4003 on p-tau Ser356 levels, it was found that WZ4003 significantly reduced p-tau Ser356 levels while increasing neuronal and synaptic protein levels.
Acta Neuropathol. 2024 Jan 4;147(1):7.
WPMY-1 cells
10 µM
24 hours
WZ4003 reduced the proliferation rate of WPMY-1 cells and increased the number of dead cells
Front Pharmacol. 2023 Apr 28;14:1105427.
Mouse organotypic brain slice cultures (MOBSCs)
5 µM
2-4 weeks
To assess the impact of WZ4003 on tau and p-tau Ser356 levels, it was found that WZ4003 significantly reduced both total tau and p-tau Ser356 levels.
Acta Neuropathol. 2024 Jan 4;147(1):7.
U2OS cells
10 µM
5 days
To evaluate the inhibitory effect of WZ4003 on U2OS cell proliferation, results showed that 10 μM WZ4003 significantly inhibited cell proliferation.
Biochem J. 2014 Jan 1;457(1):215-25.
U2OS cells
10 µM
8 hours
WZ4003 significantly reduced the population of cells in S-phase, indicating that NUAK1 inhibitors suppress proliferation by reducing S-phase cells.
Biochem J. 2014 Jul 15;461(2):233-45.
WZ4003 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
NUAK1 knockout mouse embryonic fibroblasts
In vitro culture
10 μM
Single dose, 15–20 hours
To evaluate the inhibitory effect of WZ4003 on the migration of NUAK1 knockout mouse embryonic fibroblasts, results showed that 10 μM WZ4003 significantly inhibited cell migration.
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