Cellular and pharmacological selectivity of the peroxisome proliferator-activated receptor-β/δ antagonist GSK3787

Prajakta S. Palkar, Michael G. Borland, Simone Naruhn, Christina H. Ferry, Christina Lee, Ugir H. Sk, Arun K. Sharma, Shantu Amin, Iain A. Murray, Cherie R. Anderson, Gary H. Perdew, Frank J. Gonzalez, Rolf Müller, Jeffrey M. Peters

Research output: Contribution to journalArticlepeer-review

48 Scopus citations


The availability of high-affinity agonists for peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) has led to significant advances in our understanding of the functional role of PPARβ/δ. In this study, a new PPARβ/δ 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-methylphenoxy}-acetic acid (GW0742)-induced up-regulation of Angptl4 and Adrp mRNA expression in wild-type mouse colon but not in Pparβ/δ-null mouse colon. Chromatin immunoprecipitation (ChIP) analysis indicates that this correlated with reduced promoter occupancy of PPARβ/δ on the Angptl4 and Adrp genes. Reporter assays demonstrated antagonism of PPARβ/δ activity and weak antagonism and agonism of PPARγ activity but no effect on PPARα activity. Time-resolved fluorescence resonance energy transfer assays confirmed the ability of GSK3787 to modulate the association of both PPARβ/δ and PPARγ 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 PPARγ activity is markedly lower than the efficacy of GSK3787 to act as a PPARβ/δ 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 PPARβ/δ 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.

Original languageEnglish (US)
Pages (from-to)419-430
Number of pages12
JournalMolecular pharmacology
Issue number3
StatePublished - Sep 2010

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology


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