U0126 Explained

Verifiedfields:changed
Watchedfields:changed
Verifiedrevid:447749408
Iupac Name:1,4-Diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene
Width:200px
Alt2:Space-filling model
Chembl:34704
Chebi:90693
Cas Number:218601-62-8
Unii:8027P94HLL
Pubchem:3006531
Chemspiderid:2276356
C:18
H:16
N:6
S:2
Smiles:c1cc(c(cc1)S/C(=C(/C(=C(/Sc2c(cccc2)N)\N)/C#N)\C#N)/N)N
Stdinchi: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+
Stdinchikey:DVEXZJFMOKTQEZ-JYFOCSDGSA-N

U0126[1] [2] is the 'code' name for a compound associated with cancer treatment[3] and also in preventing ischemia and cellular oxidative stress. It also has likely utility in strokes and heart attacks.[4] This compound is available for research purposes from a number of companies.[5] [6]

The specific compound is not approved by the FDA as a therapeutic agent, though it has been used in medical settings.[7] Members of this broad class of chemical compounds have been approved by the US FDA for the treatment of specific cancers.[8] [9]

It is a highly selective inhibitor of both MEK1 and MEK2, a type of MAPK/ERK kinase.[10] [11] 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.[12]

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.[13] 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.[14]

Its potential for wiping long-term memories in rats has been studied at the Center for Neural Science at New York University.[15]

See also

Notes and References

  1. Ong Q, Guo S, Zhang K, Cui B . U0126 protects cells against oxidative stress independent of its function as a MEK inhibitor . ACS Chemical Neuroscience . 6 . 1 . 130–137 . January 2015 . 25544156 . 4304487 . 10.1021/cn500288n .
  2. Web site: U-0126 . 2023-10-23 . Drug Bank . en.
  3. You Y, Niu Y, Zhang J, Huang S, Ding P, Sun F, Wang X . U0126: Not only a MAPK kinase inhibitor . Frontiers in Pharmacology . 13 . 927083 . 2022-08-25 . 36091807 . 9452634 . 10.3389/fphar.2022.927083 . free .
  4. Namura S, Iihara K, Takami S, Nagata I, Kikuchi H, Matsushita K, Moskowitz MA, Bonventre JV, Alessandrini A . 6 . Intravenous administration of MEK inhibitor U0126 affords brain protection against forebrain ischemia and focal cerebral ischemia . Proceedings of the National Academy of Sciences of the United States of America . 98 . 20 . 11569–11574 . September 2001 . 11504919 . 58770 . 10.1073/pnas.181213498 . free . 2001PNAS...9811569N .
  5. Web site: MEK Inhibitor U0126 . 2023-10-24 . www.promega.com . en.
  6. Web site: 2016-11-25 . U0126 . 2023-10-24 . InvivoGen.
  7. Cheng Y, Tian H . Current Development Status of MEK Inhibitors . Molecules . 22 . 10 . 1551 . September 2017 . 28954413 . 6151813 . 10.3390/molecules22101551 . free .
  8. Center for Drug Evaluation and Research . 2023-03-31 . FDA approves dabrafenib with trametinib for pediatric patients with low-grade glioma with a BRAF V600E mutation . FDA . en.
  9. Web site: Trametinib . 2023-10-24 . Drug Bank . en.
  10. Favata MF, Horiuchi KY, Manos EJ, Daulerio AJ, Stradley DA, Feeser WS, Van Dyk DE, Pitts WJ, Earl RA, Hobbs F, Copeland RA, Magolda RL, Scherle PA, Trzaskos JM . 6 . Identification of a novel inhibitor of mitogen-activated protein kinase kinase . The Journal of Biological Chemistry . 273 . 29 . 18623–18632 . July 1998 . 9660836 . 10.1074/jbc.273.29.18623 . 9896161 . free .
  11. DeSilva DR, Jones EA, Favata MF, Jaffee BD, Magolda RL, Trzaskos JM, Scherle PA . Inhibition of mitogen-activated protein kinase kinase blocks T cell proliferation but does not induce or prevent anergy . Journal of Immunology . 160 . 9 . 4175–4181 . May 1998 . 9574517 . 10.4049/jimmunol.160.9.4175 . 44967290 . free .
  12. Duncia JV, Santella JB, Higley CA, Pitts WJ, Wityak J, Frietze WE, Rankin FW, Sun JH, Earl RA, Tabaka AC, Teleha CA, Blom KF, Favata MF, Manos EJ, Daulerio AJ, Stradley DA, Horiuchi K, Copeland RA, Scherle PA, Trzaskos JM, Magolda RL, Trainor GL, Wexler RR, Hobbs FW, Olson RE . 6 . MEK inhibitors: the chemistry and biological activity of U0126, its analogs, and cyclization products . Bioorganic & Medicinal Chemistry Letters . 8 . 20 . 2839–2844 . October 1998 . 9873633 . 10.1016/s0960-894x(98)00522-8 .
  13. Fukazawa H, Noguchi K, Murakami Y, Uehara Y . 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 . Molecular Cancer Therapeutics . 1 . 5 . 303–309 . March 2002 . 12489846 .
  14. Web site: U0126 (CHEBI:90693) . 2024-03-05 . www.ebi.ac.uk.
  15. Smith K . 2007-03-11 . Wipe out a single memory . Nature Magazine . 2017-12-31 .

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