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Literature summary for 2.7.12.2 extracted from

  • Chapman, M.S.; Miner, J.N.
    Novel mitogen-activated protein kinase kinase inhibitors (2011), Expert Opin. Investig. Drugs, 20, 209-220.
    View publication on PubMed

Application

Application Comment Organism
drug development because of their importance in cell proliferation and signaling, MAPK pathways are being targeted for drugs for oncology, inflammation and other conditions. MEK inhibitors may be beneficial for cancer therapy. MEK inhibition is likely to be of particular importance in specific tumors where the MEK pathway is highly and directly activated Homo sapiens

Inhibitors

Inhibitors Comment Organism Structure
AS-703026 a MEK1–2 inhibitor, binds in the allosteric site of MEK1. For A-375 cells, AS-703026 has a growth IC50 of 4 nM Homo sapiens
AZD8330 ARRY424704, renamed AZD8330 Homo sapiens
BAY 869766 i.e. RDEA119 Homo sapiens
capecitabine
-
Homo sapiens
CH-4987655/RO4987655 a MEK1/2 inhibitor Homo sapiens
CH4987655 or RO4987655, a non-ATP competitive inhibitor, highly selective for MEK1 Homo sapiens
E6201 blocks proliferation of many of the cell lines typically used in testing MEK inhibitors, such as Colo205 and MiaPaca-2 Homo sapiens
GSK1120212
-
Homo sapiens
LL-Z1640-2 a MEK1 inhibitor, which shows reasonable MEK inhibition but a very short half-life Homo sapiens
additional information the MEK enzyme contains a hydrophobic allosteric pocket adjacent to the ATP-binding site which allows for the design of highly selective allosteric inhibitors Homo sapiens
PD0325901
-
Homo sapiens
PD184352/CI-1040 a allosteric, non-ATP competitive MEK inhibitor Homo sapiens
pemetrexed
-
Homo sapiens
RDEA119
-
Homo sapiens
RDEA436
-
Homo sapiens
RO4987655
-
Homo sapiens
selumetinib i.e. AZD6244, potent and highly selective, non-ATP competitive inhibitor of MEK1/2, MEK1 phosphorylation of ERK2. The compound inhibits growth of cell lines Homo sapiens
temozolomide
-
Homo sapiens
U0126 a allosteric, non-ATP competitive MEK inhibitor Homo sapiens
XL-518/GDC-0973 selective for MEK1 relative to MEK2 Homo sapiens

Metals/Ions

Metals/Ions Comment Organism Structure
Mg2+ required Homo sapiens

Natural Substrates/ Products (Substrates)

Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
ATP + ERK1/2 Homo sapiens
-
ADP + phosphorylated ERK1/2
-
?

Organism

Organism UniProt Comment Textmining
Homo sapiens
-
-
-

Source Tissue

Source Tissue Comment Organism Textmining
A-375 cell
-
Homo sapiens
-
BxPC-3 cell
-
Homo sapiens
-
Colo-205 cell
-
Homo sapiens
-
colon
-
Homo sapiens
-
HCT-116 cell
-
Homo sapiens
-
HT-29 cell
-
Homo sapiens
-
melanoma cell
-
Homo sapiens
-
MiaPaCa-2 cell
-
Homo sapiens
-
pancreas
-
Homo sapiens
-
SK-MEL-28 cell
-
Homo sapiens
-

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
ATP + ERK1/2
-
Homo sapiens ADP + phosphorylated ERK1/2
-
?

Synonyms

Synonyms Comment Organism
MAPK kinase 1
-
Homo sapiens
MAPK kinase 2
-
Homo sapiens
MEK
-
Homo sapiens
MEK1/2
-
Homo sapiens

Cofactor

Cofactor Comment Organism Structure
ATP
-
Homo sapiens

IC50 Value

IC50 Value IC50 Value Maximum Comment Organism Inhibitor Structure
0.0000052
-
inhibition of MEK1, pH and temperature not specified in the publication Homo sapiens CH4987655
0.000014
-
inhibition of MEK1 phosphorylation of ERK2, pH and temperature not specified in the publication Homo sapiens selumetinib
0.000019
-
inhibition of MEK1, pH and temperature not specified in the publication Homo sapiens BAY 869766
0.000046
-
inhibition of MEK1, pH and temperature not specified in the publication Homo sapiens LL-Z1640-2
0.000047
-
inhibition of MEK2, pH and temperature not specified in the publication Homo sapiens BAY 869766
0.000052
-
inhibition of MEK1, pH and temperature not specified in the publication Homo sapiens AS-703026

General Information

General Information Comment Organism
metabolism MAPK forms the backbone of four primary signal transduction cascades leading to the phosphorylation and activation of extracellular signal-regulated kinases 1 and 2 (ERK1-2), JNK, p38 and ERK5. The RAS-RAF-MEK-ERK pathway acts as a conduit to transduce signals from receptor tyrosine kinases (RTKs) to the nucleus. This pathway is intimately tied to intracellular machinery involved in cell proliferation, survival and cell migration, overview Homo sapiens
additional information anaphylatoxins (mainly C5a) are key players in the initiation of arthritis and utilize the MEK kinase cascade to initiate the disease process Homo sapiens
physiological function MEK signaling directly impacts both the expression of these cytokines and their downstream activation pathways Homo sapiens