Cellular and pharmacological selectivity of the peroxisome proliferator-activated receptor-beta/delta antagonist GSK3787.
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.
Palkar
Prajakta S
PS
Department of Veterinary and Biomedical Sciences and the Center for Molecular Toxicology and Carcinogenesis, the Pennsylvania State University, University Park, Pennsylvania 16802, USA.
Borland
Michael G
MG
Naruhn
Simone
S
Ferry
Christina H
CH
Lee
Christina
C
Sk
Ugir H
UH
Sharma
Arun K
AK
Amin
Shantu
S
Murray
Iain A
IA
Anderson
Cherie R
CR
Perdew
Gary H
GH
Gonzalez
Frank J
FJ
Müller
Rolf
R
Peters
Jeffrey M
JM
D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002477:Cells / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D048068:PPAR-beta / Q000235:genetics / Q000378:metabolism; D047492:Peroxisome Proliferator-Activated Receptors / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D013844:Thiazoles; D015533:Transcriptional Activation; D015854:Up-Regulation / Q000187:drug effects; D010636:Phenols; D013438:Sulfhydryl Compounds
D047493:PPAR alpha; D047495:PPAR gamma; D048068:PPAR-beta; D047492:Peroxisome Proliferator-Activated Receptors; D013844:Thiazoles; C479979:(4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid; D010636:Phenols; D013438:Sulfhydryl Compounds