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Drug-Target Interaction

Drug

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PubChem ID:3006531
Structure:
Synonyms:
(2Z,3Z)-2,3-bis[amino-(2-aminophenyl)sulfanylmethylidene]butanedinitrile
(2Z,3Z)-bis{amino[(2-aminophenyl)sulfanyl]methylidene}butanedinitrile
1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene
1,4-Diamino-2,3-dicyano-1,4-bis(o-aminophenylmercapto)butadiene
109511-58-2
5BM
AC1MHKLF
AIDS-186610
AIDS186610
BiomolKI2_000012
BiomolKI_000002
BMK1-B2
BRD-K18787491-001-04-5
BSPBio_001224
Butanedinitrile, bis(amino((2-aminophenyl)thio)methylene)-
C113580
CCG-100606
CHEBI:257660
CHEMBL34704
HMS1362N05
HMS1792N05
HMS1990N05
IDI1_002207
LS-182537
MolPort-006-069-048
NCGC00025029-02
NCGC00025029-03
NCGC00025029-04
nchembio.282-comp1
nchembio.496-comp3
SMP2_000197
Succinonitrile, bis(amino(o-aminophenylthio)methylene)-
U 0126
U-0126
U0126
U0126 cpd
U126 cpd
UO 126
UO-126
UO126

Target

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Uniprot ID:CP1A1_HUMAN
Synonyms:
CYPIA1
Cytochrome P450 1A1
P450 form 6
P450-C
P450-P1
EC-Numbers:1.14.14.1
Organism:Homo sapiens
Human
PDB IDs:-

Binding Affinities:

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

15044623
Aryl hydrocarbon receptor activation and cytochrome P450 1A induction by the mitogen-activated protein kinase inhibitor U0126 in hepatocytes.. Lise Andrieux; Sophie Langouët; Alain Fautrel; Fréderic Ezan; Joel A Krauser; Jean F Savouret; F Peter Guengerich; Georges Baffet; André Guillouzo (2004) Molecular pharmacology display abstract
The aryl hydrocarbon receptor (AhR) is involved in various processes such as cytochrome P450 (P450) 1A induction after xenobiotic exposure. It is also considered to play a major role in cell proliferation and differentiation. Recent evidences have suggested a cross-talk between AhR functions and the mitogen-activated protein kinase (MAPK) cascade. We now report that 1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio]butadiene (U0126), a specific inhibitor of MAPK kinase (MEK) MEK1/2, elicits a marked increase in CYP1A1 expression at both mRNA and protein levels associated with a significant increase of enzyme activity in primary rat hepatocytes and a human hepatoma cell line. This induction occurred independently of MEK/extracellular signal-regulated kinase (ERK) activation and in the absence of ERK1 and ERK2 expression. The effect of U0126 was mediated by its ability to transactivate xenobiotic responsive element (XRE)-driven genes, as demonstrated by transfection assays with an XRE-driven luciferase construct in the human B16A2 hepatoma cell line. CYP1A1 modulation was abolished by a cotreatment with resveratrol, an established AhR antagonist, arguing for AhR activation by U0126. Such an effect was demonstrated by direct in vitro ligand binding competition assays using rabbit liver cytosol, showing that this compound binds AhR with an EC(50) = 25 x 10(-6) M. Moreover, we demonstrated that U0126 is a substrate for several P450s including human CYP1A2, -1A1, and -1B1. We conclude that the widely used specific inhibitor of MEK/ERK, U0126, also acts as a potent AhR activator and an inducer of related genes. Such effects on the AhR may have an impact on biological functions attributed previously to MAPK inhibition.
18645229
Pharmacological inhibitors of JNK and ERK kinases SP600125 and U0126 are not appropriate tools for studies of drug metabolism because they activate aryl hydrocarbon receptor.. P Bachleda; Z Dvorák (2008) General physiology and biophysics display abstract
Mitogen-activated protein kinases (MAPKs) are important regulators of aryl hydrocarbon receptor (AhR). An immense progress in MAPKs' biochemistry was attained with the discovery of their specific pharmacological inhibitors. Unfortunately, the inhibitors of JNK and ERK MAPKs, i.e. SP600125 and U0126, respectively, affect AhR-CYP1A signaling pathway because they are partial agonists of AhR and induce CYP1A genes. This implies that SP600125 and U0126 are inappropriate tools for studies of the role of MAPKs in AhR regulation. The results from studies using SP600125 or U126, past or future, should be interpreted with prudence regarding their stimulatory effects on AhR-CYP1A pathway.