MEKs, which are members of the MAPKK family, can activate both ERK1 and ERK2 by catalyzing the phosphorylation on T202/Y204. Also MEK itself can be phosphorylated and activated through Ras when the upstream signaling is activated by extracellular stimuli, including growth factors, hormones etc.. PD98059 is MEK1/2-specific inhibitor with IC50=~10uM (measured by phosphorylation level of MAPK-KA catalyzed by GST-MEK1) with no effect on ERK. Pre-incubation of PD98059 can inhibit PDGF-stimulated tyrosine phosphorylation of MAPK while preventing thymidine incorporation with an IC50 of 7 uM in 3T3 cells. PD98059 did not show significant inhibitory activity on Raf kinase, cAMP-dependent kinase, protein kinase C, v-Src, EGF receptor kinase, insulin receptor kinase, PDGFreceptor kinase, and PI3Ks, which shows the high selectivity of it [1]. PD98059 is the first generation small molecule inhibitors of MEK1/2. PD98059 does not interfere with Raf access to MEK1/2 for it did not affect serum-induced MEK1/2 phosphorylation [2].
作用机制
PD 098059 does not complete for ATP binding or MAPK binding to MEK and most likely inhibits through an allosteric mechanism.[1]
PD98059 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Human intrahepatic biliary epithelial cells (HIBEpiCs)
10 μM
24 h
Pretreatment with PD98059 reduced apelin-induced ERK phosphorylation and cholangiocyte proliferation
To evaluate the effects of PD98059 on the metabolic activity and cytotoxicity of Y79 cells. PD98059 significantly inhibited cellular metabolic activity at a concentration of 3.12 µM or higher, but did not significantly increase cytotoxicity.
To evaluate the effects of PD98059 on the metabolic activity and cytotoxicity of huPMCs cells. PD98059 did not significantly inhibit cellular metabolic activity at concentrations up to 12.5 µM, nor did it significantly increase cytotoxicity.
To evaluate the effects of PD98059 on the metabolic activity and cytotoxicity of MIO-M1 cells. PD98059 significantly inhibited cellular metabolic activity at a concentration of 1.56 µM or higher, but did not significantly increase cytotoxicity.
Theranostics. 2022 Sep 11;12(15):6705-6722.
U87 cells
5 μM
12 h
To investigate the effect of PD98059 on RRM2 overexpression in U87 cells, the results showed that PD98059 inhibited the phosphorylation of ERK1/2 and blocked the upregulation of cyclin B1, cyclin D1, and N-cadherin expression induced by RRM2 overexpression.
Int J Biol Sci. 2019 Jan 1;15(3):533-543.
Human adipose-derived stem cells (hASCs)
5 μM
48 h
To investigate the effect of PD98059 on FGF-2-mediated proliferation of hASCs, results showed that PD98059 significantly inhibited FGF-2-mediated cell proliferation.
Stem Cell Res Ther. 2019 Nov 27;10(1):350.
human adipose tissue-derived stem cells (hADSCs)
40 μM
30 min
PD98059 abolished the ERK1/2 phosphorylation and proliferation induced by silica NPs
Int J Nanomedicine. 2015 Mar 24;10:2261-72.
MIA-PaCa-2 cells
25 µM
PD98059 completely blocked KIF15-mediated pancreatic cancer cell proliferation
Br J Cancer. 2017 Jul 11;117(2):245-255.
PANC-1 cells
25 µM
PD98059 completely blocked KIF15-mediated pancreatic cancer cell proliferation
Br J Cancer. 2017 Jul 11;117(2):245-255.
PD98059 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
Photo-oxidative damage model
Intravitreal injection
100 µM
Single injection, lasting 4 days
To evaluate the protective effects of PD98059 on the retina of photo-oxidative damage mice. PD98059 significantly inhibited the phosphorylation of pERK1/2, reduced the expression of the gliotic marker GFAP in Müller cells, and increased the levels of the neuroprotective factor IRBP in photoreceptors. PD98059 also reduced photoreceptor apoptosis in photo-oxidative damage mice and assessed its protective effects on retinal function through OCT and ERG.
Theranostics. 2022 Sep 11;12(15):6705-6722.
Balb/c nude mice
Orthotopic pancreatic cancer transplantation model
Subcutaneous injection
10 mg/kg
Once daily for 9 weeks
PD98059 blocked KIF15-mediated pancreatic cancer proliferation and prolonged the survival time of mice
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