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Cellular and pharmacological selectivity of the peroxisome proliferator-activated receptor-beta/delta antagonist GSK3787.

Abstract：

:The availability of high-affinity agonists for peroxisome proliferator-activated receptor-beta/delta (PPARbeta/delta) has led to significant advances in our understanding of the functional role of PPARbeta/delta. In this study, a new PPARbeta/delta antagonist, 4-chloro-N-(2-{[5-trifluoromethyl)-2-pyridyl]sulfonyl}ethyl)benzamide (GSK3787), was characterized using in vivo and in vitro models. Orally administered GSK3787 caused antagonism of 4-[2-(3-fluoro-4-trifluoromethyl-phenyl)-4-methyl-thiazol-5-ylmethylsulfanyl]-2-methyl-phenoxy}-acetic acid (GW0742)-induced up-regulation of Angptl4 and Adrp mRNA expression in wild-type mouse colon but not in Pparbeta/delta-null mouse colon. Chromatin immunoprecipitation (ChIP) analysis indicates that this correlated with reduced promoter occupancy of PPARbeta/delta on the Angptl4 and Adrp genes. Reporter assays demonstrated antagonism of PPARbeta/delta activity and weak antagonism and agonism of PPARgamma activity but no effect on PPARalpha activity. Time-resolved fluorescence resonance energy transfer assays confirmed the ability of GSK3787 to modulate the association of both PPARbeta/delta and PPARgamma coregulator peptides in response to ligand activation, consistent with reporter assays. In vivo and in vitro analysis indicates that the efficacy of GSK3787 to modulate PPARgamma activity is markedly lower than the efficacy of GSK3787 to act as a PPARbeta/delta antagonist. GSK3787 antagonized GW0742-induced expression of Angptl4 in mouse fibroblasts, mouse keratinocytes, and human cancer cell lines. Cell proliferation was unchanged in response to either GW0742 or GSK3787 in human cancer cell lines. Results from these studies demonstrate that GSK3787 can antagonize PPARbeta/delta in vivo, thus providing a new strategy to delineate the functional role of a receptor with great potential as a therapeutic target for the treatment and prevention of disease.

journal_name

Mol Pharmacol

journal_title

Molecular pharmacology

authors

Palkar PS,Borland MG,Naruhn S,Ferry CH,Lee C,Sk UH,Sharma AK,Amin S,Murray IA,Anderson CR,Perdew GH,Gonzalez FJ,Müller R,Peters JM

doi

10.1124/mol.110.065508

subject

Has Abstract

pub_date

2010-09-01 00:00:00

pages

419-30

issue

3

eissn

0026-895X

issn

1521-0111

pii

mol.110.065508

journal_volume

78

pub_type

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