U0126

U0126

Identifiers
IUPAC name 1,4-diamino-2,3-dicyano-1,4-bis (2-aminophenylthio)butadiene
CAS Number	218601-62-8
PubChem (CID)	3006531
ChemSpider	2276356
UNII	8027P94HLL
ChEBI	CHEBI:90693
ChEMBL	CHEMBL34704
Chemical and physical data
Formula	C18H16N6S2
Molar mass	380.49 g/mol
3D model (Jmol)	Interactive image
SMILES c1cc(c(cc1)S/C(=C(/C(=C(/Sc2c(cccc2)N)\N)/C#N)\C#N)/N)N
InChI InChI=1S/C18H16N6S2/c19-9-11(17(23)25-15-7-3-1-5-13(15)21)12(10-20)18(24)26-16-8-4-2-6-14(16)22/h1-8H,21-24H2/b17-11+,18-12+ Key:DVEXZJFMOKTQEZ-JYFOCSDGSA-N
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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, Cdk2 and Cdk4.

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)