Uses
A chemically synthesized and highly selective inhibitor of both MEK1 and MEK2 with IC50s of 70 nM and 60 nM, respectively.
Definition
ChEBI: U0126.EtOH is an addition compound obtained by combining equimolar amounts of (2Z,3Z)-bis{amino[(2-aminophenyl)sulfanyl]methylidene}butanedinitrile (U0126) and ethanol. An inhibitor of mitogen-activated protein kinase that also exhibits anti-cancer properties. It has a role as an EC 2.7.11.24 (mitogen-activated protein kinase) inhibitor, an apoptosis inducer, an antineoplastic agent, an antioxidant, an osteogenesis regulator and a vasoconstrictor agent. It contains an U0126.
Biological Activity
u0126-etoh is a selective inhibitor of mek1 and mek2 with ic50 values of 70 nm and 60 nm, resepctively [1].u0126 was screened out as an anti-inflammatory agent that inhibited ap-1 transcription with ic50 value of 1μm and had no interactions with gres. u0126 binds mek1/2 in a unique site. this inhibition of mek1/2 is noncompetitive with erk and atp. u0126 showed no effects on other mapkks. in ht22 cells, u0126 treatment significantly inhibited the cell injury caused by oxidative glutamate toxicity and remarkably blocked the phosphorylation of erk1/2. besides that, u0126 exerted no neuroprotection against other stimuli such as tnfα and actinomycin d. u0126 treatment also protected the primary cultured cortical neurons from oxidative glutamate toxicity and hypoxia/reoxygenation [1, 2].
in vivo
Mice are treated daily with U0126-EtOH (U0126; i.p., 10.5 mg/kg). In control experiment, tumor sizes are constant or slightly increase all over the kinetic. At the opposite, in all U0126-EtOH experiments, engraftment and early tumor growth are significantly decreased. Furthermore, a 60-70% reduction in the volume of tumors treated with U0126-EtOH is obtained 9 days after injection and thereafter[3].
Rats are subjected to 120 minutes transient middle cerebral artery occlusion (tMCAO) and thereafter treated with the U0126-EtOH (U0126; i.p., 30 mg/kg) at 0 and 24 hours of reperfusion. After treatment with U0126-EtOH, the vasoconstriction to S6c is markedly reduced[4].
| Animal Model: | Athymic female nude mice (SWISS, nu/nu)[3]. |
| Dosage: | 10.5 mg/kg. |
| Administration: | Intraperitoneal injection daily. |
| Result: | Inhibited tumor growth. |
| Animal Model: | Twelve-week-old female Wistar rats (250 to 265 g)[4]. |
| Dosage: | 30 mg/kg. |
| Administration: | Intraperitoneally. |
| Result: | The vasoconstriction to S6c is markedly reduced. |
IC 50
MEK2: 60 nM (IC
50); MEK1: 70 nM (IC
50)
References
[1] duncia j v, santella iii j b, higley c a, et al. mek inhibitors: the chemistry and biological activity of u0126, its analogs, and cyclization products. bioorganic & medicinal chemistry letters, 1998, 8(20): 2839-2844.
[2] satoh t, nakatsuka d, watanabe y, et al. neuroprotection by mapk/erk kinase inhibition with u0126 against oxidative stress in a mouse neuronal cell line and rat primary cultured cortical neurons. neuroscience letters, 2000, 288(2): 163-166.
