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Drug-Target Interaction

Drug

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PubChem ID:4306515
Structure:
Synonyms:
1H-Pyrazole, 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-
5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)pyrazole
5-(4-Chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethyl pyrazole
5-(4-Chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethylpyrazole
AC1N7Q9I
BRD-K14767410-001-01-5
C115461
CCG-205163
CHEMBL26915
EC-000.2441
EU-0101086
IN1103
Lopac-S-2064
Lopac0_001086
LS-128397
NCGC00015933-01
NCGC00015933-02
NCGC00015933-03
NCGC00015933-04
NCGC00094361-01
NCGC00094361-02
NCGC00094361-03
nchembio.364-comp5
S 2064
S2064_SIGMA
SC 560
SC-560
SC560
TL80090035
ZINC02391787

Target

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Uniprot ID:MK03_HUMAN
Synonyms:
ERK-1
ERT2
Extracellular signal-regulated kinase 1
Insulin-stimulated MAP2 kinase
MAP kinase 1
MAPK 1
Microtubule-associated protein 2 kinase
Mitogen-activated protein kinase 3
p44-ERK1
p44-MAPK
EC-Numbers:2.7.11.24
Organism:Homo sapiens
Human
PDB IDs:2ZOQ
Structure:
2ZOQ

Binding Affinities:

Ki: Kd:Ic 50:Ec50/Ic50:
----

References:

18424914
Potentiation of the antitumor effects of both selective cyclooxygenase-1 and cyclooxygenase-2 inhibitors in human hepatic cancer cells by inhibition of the MEK/ERK pathway.. Antonella Cusimano; Daniela FoderÓ; Natale D'Alessandro; Nadia Lampiasi; Antonina Azzolina; Giuseppe Montalto; Melchiorre Cervello (2007) Cancer biology & therapy display abstract
The molecular mechanisms behind the anti-neoplastic effects of non-steroidal anti-inflammatory drugs (NSAIDs) are not completely understood and cannot be explained by the inhibition of the cyclooxygenase (COX) enzymes COX-1 and COX-2 alone. We previously reported that both the selective COX-1 inhibitor SC-560 and the selective COX-2 inhibitor CAY10404 exhibit anti-tumor effects in human hepatoma cells. NSAID inhibitors have many COX-independent actions and, among others, the mitogen-activated protein kinase (MAPK) pathways are targets for NSAIDs. Here, we examined the role of MEK/ERK1/2 signaling in the anti-neoplastic effects of both selective COX-1 and COX-2 inhibitors in two human hepatoma cell lines. Treatment of hepatoma cells with the selective COX-1 inhibitor SC-560, as well as with the selective COX-2 inhibitor CAY10404, was associated with activation of ERK1/2 in a time- and dose-dependent manner. Treatment with COX-1 and COX-2 inhibitors in the presence of the selective MEK1/2 inhibitor U0126 effectively suppressed ERK1/2 activation and combinations of either SC-560 or CAY10404 with U0126 resulted in synergistic effects on cell growth inhibition and induction of apoptosis. In HuH-6 hepatoma cells the combination-induced apoptosis was associated with caspase-9 and -3 activation, PARP cleavage, release of cytochrome c from the mitochondria into the cytosol and down-regulation of survivin and beta-catenin levels. In conclusion, our study showed that growth inhibitory concentrations of selective COX-1 and COX-2 inhibitors increased ERK1/2 phosphorylation in hepatoma cells, and that inhibition of the MEK/ERK signaling pathway potentiates the antitumor activity of both types of inhibitors. Therefore, our results provide preclinical support for a combined chemotherapeutic approach with selective NSAIDs and MEK inhibitors for the treatment of hepatocellular carcinoma.