MNK1 is important for its regulation of phosphorylation of eIF4E mediated via the activation of MAP kinase pathways. CGP57380 is a MNK1 inhibitor with IC50 values of 2.2μM and 3μM for inhibition of MNK1 kinase activity in vitro and phosphorylation of eIF4E in cellular assays, respectively. Pretreatment with CGP57380 at concentration of 10μM for 60min could block phosphorylation of eIF4E induced by TNF-α, arsenite, anisomycin, PMA or FCS in 293 cells. Meanwhile, inhibition of MNK1 by CGP-57380 resulted in a dose-dependent increase in the activity of cap-dependent translation in a reporter gene assay with reduced eIF4E phosphorylation in 293 cells. CGP57380 at concentration ranging in 1-10μM resulted in dose-dependent decreases in Ang II–stimulated phosphorylation of eIF4E, protein synthesis, and VSMC hypertrophy of VSMCs. CGP-57380 prevented eIF4E phosphorylation, β-catenin activation, and BC LSC function in vitro at concentration of 10μM and in vivo at dose of 40mg/kg, intraperitoneally, daily, for 3 weeks.
CGP 57380 细胞实验
Cell Line
Concentration
Treated Time
Description
References
NP69
273.44 µM
72 h
Low toxicity to normal cells
Theranostics. 2017 May 30;7(7):2134-2149.
HNE1
103.278 µM
72 h
Inhibition of cell proliferation and colony formation ability
Theranostics. 2017 May 30;7(7):2134-2149.
CNE1
38.261 µM
72 h
Inhibition of cell proliferation and colony formation ability
Theranostics. 2017 May 30;7(7):2134-2149.
U87MG-luc cells
10 μM
3 days
MTT assay showed that combined treatment with CGP57380 and RAD001 significantly inhibited cell proliferation.
J Clin Invest. 2014 Feb;124(2):742-54.
LN229 cells
10 μM
20 h
Western blot analysis showed that CGP57380 or MNK1 siRNA combined with RAD001 significantly inhibited 4EBP1 phosphorylation at Ser65.
J Clin Invest. 2014 Feb;124(2):742-54.
U373 cells
10 μM
20 h
Analyzed how MNK1 and mTORC1 signaling pathways regulate the assembly of translation initiation complexes, found that CGP57380 or MNK1 knockdown combined with RAD001 increased 4EBP1 binding to eIF4E.
J Clin Invest. 2014 Feb;124(2):742-54.
CEM cells
4-16 μM
24 h
CGP57380 dose-dependently suppressed the expression of both phosphor-MNK1 and phosphor-eIF4E, thereby inhibiting downstream targets such as c-Myc and survivin.
Acta Pharmacol Sin. 2018 Dec;39(12):1894-1901.
Jurkat cells
4-16 μM
24 h
CGP57380 dose-dependently suppressed the expression of both phosphor-MNK1 and phosphor-eIF4E, thereby inhibiting downstream targets such as c-Myc and survivin.
Acta Pharmacol Sin. 2018 Dec;39(12):1894-1901.
A549 cells
20 μM
CGP57380 substantially reduced eIF4G in the eIF4F complex while drastically inhibiting eIF4E phosphorylation
Neoplasia. 2010 Oct;12(10):848-55.
H157 cells
10-40 μM
30 min pretreatment followed by 4 h co-treatment
CGP57380 reduced basal p-eIF4E levels and almost completely blocked OA-induced increase in eIF4E phosphorylation
Neoplasia. 2010 Oct;12(10):848-55.
CGP 57380 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Nude mice
Orthotopic GBM mouse model
I.p. injection
25 mg/kg
4 injections between days 8 and 15 after implantation
Evaluated the effects of CGP57380 alone or in combination with RAD001 in vivo, found that combined treatment significantly inhibited tumor growth.
J Clin Invest. 2014 Feb;124(2):742-54.
BALB/c nude mice
Subcutaneous tumor model
Intraperitoneal injection
25 mg/kg
Three times per week for 3 weeks
Inhibition of tumor growth and metastasis
Theranostics. 2017 May 30;7(7):2134-2149.
C57BL/6 mice
LPS-induced acute lung injury model
Intraperitoneal injection
30 mg/kg
Single dose, pretreated for 30 min before LPS challenge
To evaluate the protective effect of CGP57380 on LPS-induced acute lung injury. Results showed that CGP57380 pretreatment significantly attenuated LPS-induced lung wetry ratio, protein content, total cells and neutrophils in BALF, and decreased the production of pro-inflammatory mediators such as IL-6, TNF-α, and KC.
Biochem Pharmacol. 2021 Apr;186:114499
Sprague-Dawley rats
Experimental model of brain stem death
Bilateral microinjection into RVLM
5 pmol
Single administration, observed for 180 minutes
To evaluate the effect of CGP57380 on cardiovascular regulation in the brain stem death model. Results showed that CGP57380 pretreatment exacerbated hypotension and blunted the life signal, shortening the pro-life phase.
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