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
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 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.[ citation needed ]

Its potential for wiping long-term memories in rats has been studied at the Center for Neural Science at New York University. [14]

See also

Related Research Articles

A mitogen-activated protein kinase is a type of protein kinase that is specific to the amino acids serine and threonine. MAPKs are involved in directing cellular responses to a diverse array of stimuli, such as mitogens, osmotic stress, heat shock and proinflammatory cytokines. They regulate cell functions including proliferation, gene expression, differentiation, mitosis, cell survival, and apoptosis.

Biological crosstalk refers to instances in which one or more components of one signal transduction pathway affects another. This can be achieved through a number of ways with the most common form being crosstalk between proteins of signaling cascades. In these signal transduction pathways, there are often shared components that can interact with either pathway. A more complex instance of crosstalk can be observed with transmembrane crosstalk between the extracellular matrix (ECM) and the cytoskeleton.

Anoikis is a form of programmed cell death that occurs in anchorage-dependent cells when they detach from the surrounding extracellular matrix (ECM). Usually cells stay close to the tissue to which they belong since the communication between proximal cells as well as between cells and ECM provide essential signals for growth or survival. When cells are detached from the ECM, there is a loss of normal cell–matrix interactions, and they may undergo anoikis. However, metastatic tumor cells may escape from anoikis and invade other organs.

Mitogen Activated Protein (MAP) kinase kinase kinase is a serine/threonine-specific protein kinase which acts upon MAP kinase kinase. Subsequently, MAP kinase kinase activates MAP kinase. Several types of MAPKKK can exist but are mainly characterized by the MAP kinases they activate. MAPKKKs are stimulated by a large range of stimuli, primarily environmental and intracellular stressors. MAPKKK is responsible for various cell functions such as cell proliferation, cell differentiation, and apoptosis. The duration and intensity of signals determine which pathway ensues. Additionally, the use of protein scaffolds helps to place the MAPKKK in close proximity with its substrate to allow for a reaction. Lastly, because MAPKKK is involved in a series of several pathways, it has been used as a therapeutic target for cancer, amyloidosis, and neurodegenerative diseases. In humans, there are at least 19 genes which encode MAP kinase kinase kinases:

The MAPK/ERK pathway is a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell.

In molecular biology, extracellular signal-regulated kinases (ERKs) or classical MAP kinases are widely expressed protein kinase intracellular signalling molecules that are involved in functions including the regulation of meiosis, mitosis, and postmitotic functions in differentiated cells. Many different stimuli, including growth factors, cytokines, virus infection, ligands for heterotrimeric G protein-coupled receptors, transforming agents, and carcinogens, activate the ERK pathway.

Mitogen-activated protein kinase kinase is a dual-specificity kinase enzyme which phosphorylates mitogen-activated protein kinase (MAPK).

<span class="mw-page-title-main">MAPK1</span> Protein-coding gene in the species Homo sapiens

Mitogen-activated protein kinase 1, also known as ERK2, is an enzyme that in humans is encoded by the MAPK1 gene.

<span class="mw-page-title-main">MAPK3</span> Protein-coding gene in the species Homo sapiens

Mitogen-activated protein kinase 3, also known as p44MAPK and ERK1, is an enzyme that in humans is encoded by the MAPK3 gene.

<span class="mw-page-title-main">MAP2K1</span> Protein-coding gene in the species Homo sapiens

Dual specificity mitogen-activated protein kinase kinase 1 is an enzyme that in humans is encoded by the MAP2K1 gene.

<span class="mw-page-title-main">MAP2K2</span> Protein-coding gene in the species Homo sapiens

Dual specificity mitogen-activated protein kinase kinase 2 is an enzyme that in humans is encoded by the MAP2K2 gene. It is more commonly known as MEK2, but has many alternative names including CFC4, MKK2, MAPKK2 and PRKMK2.

<span class="mw-page-title-main">ELK1</span> Protein-coding gene in humans

ETS Like-1 protein Elk-1 is a protein that in humans is encoded by the ELK1. Elk-1 functions as a transcription activator. It is classified as a ternary complex factor (TCF), a subclass of the ETS family, which is characterized by a common protein domain that regulates DNA binding to target sequences. Elk1 plays important roles in various contexts, including long-term memory formation, drug addiction, Alzheimer's disease, Down syndrome, breast cancer, and depression.

<span class="mw-page-title-main">MAP2K3</span> Protein-coding gene in the species Homo sapiens

Dual specificity mitogen-activated protein kinase kinase 3 is an enzyme that in humans is encoded by the MAP2K3 gene.

<span class="mw-page-title-main">ARAF</span> Protein-coding gene in humans

Serine/threonine-protein kinase A-Raf or simply A-Raf is an enzyme that in humans is encoded by the ARAF gene. A-Raf is a member of the Raf kinase family of serine/threonine-specific protein kinases.

<span class="mw-page-title-main">MAP3K1</span> Protein-coding gene in the species Homo sapiens

Mitogen-activated protein kinase kinase kinase 1 (MAP3K1) is a signal transduction enzyme that in humans is encoded by the autosomal MAP3K1 gene.

<span class="mw-page-title-main">RPS6KA2</span> Enzyme found in humans

Ribosomal protein S6 kinase alpha-2 is an enzyme that in humans is encoded by the RPS6KA2 gene.

<span class="mw-page-title-main">MAP2K1IP1</span> Protein-coding gene in the species Homo sapiens

Mitogen-activated protein kinase scaffold protein 1 is a scaffold protein that in humans is encoded by the MAPKSP1 gene.

<span class="mw-page-title-main">Selumetinib</span> Chemical compound

Selumetinib (INN), sold under the brand name Koselugo, is a medication for the treatment of children, two years of age and older, with neurofibromatosis type I (NF-1), a genetic disorder of the nervous system causing tumors to grow on nerves. It is taken by mouth.

A MEK inhibitor is a chemical or drug that inhibits the mitogen-activated protein kinase kinase enzymes MEK1 and/or MEK2. They can be used to affect the MAPK/ERK pathway which is often overactive in some cancers.

<span class="mw-page-title-main">Binimetinib</span> Chemical compound

Binimetinib, sold under the brand name Mektovi, is an anti-cancer medication used to treat various cancers. Binimetinib is a selective inhibitor of MEK, a central kinase in the tumor-promoting MAPK pathway. Inappropriate activation of the pathway has been shown to occur in many cancers. In June 2018 it was approved by the FDA in combination with encorafenib for the treatment of patients with unresectable or metastatic BRAF V600E or V600K mutation-positive melanoma. In October 2023, it was approved by the FDA for treatment of NSCLC with a BRAF V600E mutation in combination with encorafenib. It was developed by Array Biopharma.

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. Retrieved 2023-10-23.
  3. ↑ 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.
  4. ↑ 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.
  5. ↑ "MEK Inhibitor U0126". www.promega.com. Retrieved 2023-10-24.
  6. ↑ "U0126". InvivoGen. 2016-11-25. Retrieved 2023-10-24.
  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. ↑ 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.
  9. ↑ "Trametinib". Drug Bank. Retrieved 2023-10-24.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ Smith K (2007-03-11). "Wipe out a single memory". Nature Magazine. Retrieved 2017-12-31.
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