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BioAssay: AID 455694

Agonist activity at human full length HNF4alpha nuclear receptor expressed in human HepG2/C3A cells co-transfected with LexADBD assessed as increase in transcriptional activity at 6.2 uM by beta-galactosidase one hybrid assay relative to control

Nuclear receptors are ligand-activated transcription factors involved in all major physiological functions of complex organisms. In this respect, they are often described as drugable targets for a number of pathological states including hypercholesterolemia and atherosclerosis. HNF4alpha (NR2A1) is a recently 'deorphanized' nuclear receptor which is bound in vivo by linoleic acid, although this more ..
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Unspecified(1)
 
 
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AID: 455694
Data Source: ChEMBL (606752)
Depositor Category: Literature, Extracted
BioAssay Version:
Deposit Date: 2010-07-30
Modify Date: 2014-08-24

Data Table ( Complete ):           View All Data
Target
Sequence: RecName: Full=Hepatocyte nuclear factor 4-alpha; Short=HNF-4-alpha; AltName: Full=Nuclear receptor subfamily 2 group A member 1; AltName: Full=Transcription factor 14; Short=TCF-14; AltName: Full=Transcription factor HNF-4
Description ..   
Protein Family: The ligand binding domain of heptocyte nuclear factor 4, which is explosively expanded in nematodes
Comment ..   

Gene:HNF4A     Related Protein 3D Structures     More BioActivity Data..
Tested Compound:
Description:
Title: Identification of small molecule regulators of the nuclear receptor HNF4alpha based on naphthofuran scaffolds.

Abstract: Nuclear receptors are ligand-activated transcription factors involved in all major physiological functions of complex organisms. In this respect, they are often described as drugable targets for a number of pathological states including hypercholesterolemia and atherosclerosis. HNF4alpha (NR2A1) is a recently 'deorphanized' nuclear receptor which is bound in vivo by linoleic acid, although this natural ligand does not seem to promote transcriptional activation. In mouse, HNF4alpha is a major regulator of liver development and hepatic lipid metabolism and mutations in human have been linked to diabetes. Here, we have used a yeast one-hybrid system to identify small molecule activators of HNF4alpha in a library of synthetic compounds and found one hit bearing a methoxy group branched on a nitronaphthofuran backbone. A collection of molecules deriving from the discovered hit was generated and tested for activity toward HNF4alpha in yeast one-hybrid system. It was found that both the nitro group and a complete naphthofuran backbone were required for full activity of the compounds. Furthermore, adding a hydroxy group at position 7 of the minimal backbone led to the most active compound of the collection. Accordingly, a direct interaction of the hydroxylated compound with the ligand binding domain of HNF4alpha was detected by NMR and thermal denaturation assays. When used in mammalian cell culture systems, these compounds proved to be highly toxic, except when methylated on the furan ring. One such compound was able to modulate HNF4alpha-driven transcription in transfected HepG2C3A cells. These data indicate that HNF4alpha activity can be modulated by small molecules and suggest new routes for targeting the receptor in humans.
(PMID: 19729315)
Categorized Comment - additional comments and annotations
From BioAssay Depositor:
Assay Type: Functional
Target Type: Target is a single protein chain
Assay Data Source: Scientific Literature
BAO: Assay Format: cell-based format
Assay Test Type: In vitro
Result Definitions
TIDNameDescriptionHistogramTypeUnit
OutcomeThe BioAssay activity outcomeOutcome
1Fold change activity commentFold change activity commentString
2Fold change standard flagFold change standard flagInteger
3Fold change qualifierFold change qualifierString
4Fold change published valueFold change published valueFloat
5Fold change standard valueFold change standard valueFloat

Data Table (Concise)
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