U0126

Last updated
U0126
U0126.svg
U0126-3D-spacefill.png
Identifiers
  • 1,4-Diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene
CAS Number
PubChem CID
ChemSpider
UNII
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C18H16N6S2
Molar mass 380.49 g·mol−1
3D model (JSmol)
  • c1cc(c(cc1)S/C(=C(/C(=C(/Sc2c(cccc2)N)\N)/C#N)\C#N)/N)N
  • 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+ X mark.svgN
  • Key:DVEXZJFMOKTQEZ-JYFOCSDGSA-N X mark.svgN
 X mark.svgNYes check.svgY  (what is this?)    (verify)

U0126 [1] [2] is a MEK1/ 2 inhibitor that is used to study MEK and related signaling pathways. This inhibitor is selective for both MEK1 and MEK2, [3] [4] two specific types of MEK (MAPK kinases) that are elements of the MAPK/ERK signaling pathway. This compound is usually studied in the context of cancer treatment, [5] ischemia, [6] and cellular oxidative stress.

The compound is not approved by the FDA as a therapeutic agent, and is primarily used in preclinical research settings. [7] This compound is available for research purposes from a number of companies. [8] [9]

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. [10] U0126 is selective for MEK and has little to no effect on other signaling molecules such as PKC, Raf, ERK, JNK, MEKK, MKK-3, MKK-4/SEK, MKK-6, Cdk2 and Cdk4. [11]

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. [12] 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.

Its potential for wiping long-term memories in rats has been studied at the Center for Neural Science at New York University. [13]

See also

References

  1. ↑ Ong Q, Guo S, Zhang K, Cui B (January 2015). "U0126 protects cells against oxidative stress independent of its function as a MEK inhibitor". ACS Chemical Neuroscience. 6 (1): 130–137. doi:10.1021/cn500288n. PMC   4304487 . PMID   25544156.
  2. ↑ "U-0126". Drug Bank. Archived from the original on 2024-06-11. Retrieved 2023-10-23.
  3. ↑ Favata MF, Horiuchi KY, Manos EJ, Daulerio AJ, Stradley DA, Feeser WS, et al. (July 1998). "Identification of a novel inhibitor of mitogen-activated protein kinase kinase". The Journal of Biological Chemistry. 273 (29): 18623–18632. doi: 10.1074/jbc.273.29.18623 . PMID   9660836. S2CID   9896161.
  4. ↑ DeSilva DR, Jones EA, Favata MF, Jaffee BD, Magolda RL, Trzaskos JM, Scherle PA (May 1998). "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. doi: 10.4049/jimmunol.160.9.4175 . PMID   9574517. S2CID   44967290.
  5. ↑ You Y, Niu Y, Zhang J, Huang S, Ding P, Sun F, Wang X (2022-08-25). "U0126: Not only a MAPK kinase inhibitor". Frontiers in Pharmacology. 13: 927083. doi: 10.3389/fphar.2022.927083 . PMC   9452634 . PMID   36091807.
  6. ↑ Namura S, Iihara K, Takami S, Nagata I, Kikuchi H, Matsushita K, et al. (September 2001). "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. Bibcode:2001PNAS...9811569N. doi: 10.1073/pnas.181213498 . PMC   58770 . PMID   11504919.
  7. ↑ Cheng Y, Tian H (September 2017). "Current Development Status of MEK Inhibitors". Molecules. 22 (10): 1551. doi: 10.3390/molecules22101551 . PMC   6151813 . PMID   28954413.
  8. ↑ "MEK Inhibitor U0126". www.promega.com. Archived from the original on 2021-06-20. Retrieved 2023-10-24.
  9. ↑ "U0126". InvivoGen. 2016-11-25. Archived from the original on 2023-09-26. Retrieved 2023-10-24.
  10. ↑ Duncia JV, Santella JB, Higley CA, Pitts WJ, Wityak J, Frietze WE, et al. (October 1998). "MEK inhibitors: the chemistry and biological activity of U0126, its analogs, and cyclization products". Bioorganic & Medicinal Chemistry Letters. 8 (20): 2839–2844. doi:10.1016/s0960-894x(98)00522-8. PMID   9873633.
  11. ↑ Favata MF, Horiuchi KY, Manos EJ, Daulerio AJ, Stradley DA, Feeser WS, et al. (July 1998). "Identification of a novel inhibitor of mitogen-activated protein kinase kinase". The Journal of Biological Chemistry. 273 (29): 18623–18632. doi: 10.1074/jbc.273.29.18623 . PMID   9660836.
  12. ↑ Fukazawa H, Noguchi K, Murakami Y, Uehara Y (March 2002). "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. PMID   12489846.
  13. ↑ Smith K (2007-03-11). "Wipe out a single memory". Nature Magazine. Retrieved 2017-12-31.
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