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U0126

U0126
Systematic (IUPAC) name
1,4-diamino-2,3-dicyano-1,4-bis
(2-aminophenylthio)butadiene
Identifiers
CAS number  ?
ATC code  ?
PubChem  ?
Chemical data
Formula C18H16N6S2 
Mol. mass 380.49 g/mol
Pharmacokinetic data
Bioavailability  ?
Metabolism  ?
Half life  ?
Excretion  ?
Therapeutic considerations
Pregnancy cat.

?
Legal status
Routes  ?

U0126, is a highly selective inhibitor of both MEK1 and MEK2, a type of MAPK/ERK kinase. U0126 was found to functionally antagonize AP-1 transcriptional activity via noncompetitive inhibition of the dual specificity kinase MEK with IC50 of 72 nM for MEK1 and 58 nM for MEK2. U0126 inhibited anchorage-independent growth of Ki-ras-transformed rat fibroblasts by simultaneously blocking both extracellular signal-regulated kinase (ERK) and mammalian target of rapamycin (mTOR)-p70(S6K) pathways. The effects of U0126 on the growth of eight human breast cancer cell lines shown that U0126 selectively repressed anchorage-independent growth of MDA-MB231 and HBC4 cells, two lines with constitutively activated ERK. Loss of contact with substratum triggers apoptosis in many normal cell types, a phenomenon termed anoikis. U0126 sensitized MDA-MB231 and HBC4 to anoikis, i.e., upon treatment with U0126, cells deprived of anchorage entered apoptosis.

U0126 is also a weak inhibitor of PKC, Raf, ERK, JNK, MEKK, MKK-3, MKK-4/SEK, MKK-6, Abl, Cdk2 and Cdk4

It is also known to cause limited amnesia, and there seems to be some evidence that this compound could be of use for the treatment of post-traumatic stress disorder.

references

  • Favata, M., et al., Identification of a novel inhibitor of mitogen-activated protein kinase. J. Biol. Chem. 273, 18623, (1998)
  • DeSilva, D., et al., Inhibition of mitogen-activated protein kinase blocks T cell proliferation but does not induce or prevent anergy. J. Immunol. 160, 4175, (1998)
  • Duncia, J.V., et al., MEK inhibitors: The chemistry and biological activity of U0126, its analogs, and cyclization products. Bioorg. Med. Chem. Lett. 8, 2839-2844, (1998)
  • Fukazawa, H., et al.,, Mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) inhibitors restore anoikis sensitivity in human breast cancer cell lines with a constitutively activated extracellular-regulated kinase (ERK) pathway. Mol. Cancer Ther., 303-309, (2002)
  • Wipe out a single memory- Nature http://www.nature.com/news/2007/070305/full/070305-17.html
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