Cellular and Pharmacological Selectivity of the Peroxisome Proliferator-Activated Receptor- / Antagonist GSK3787

The availability of high-affinity agonists for peroxisome proliferator-activated receptor/ (PPAR / ) has led to significant advances in our understanding of the functional role of PPAR / . In this study, a new PPAR / 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 Ppar / -null mouse colon. Chromatin immunoprecipitation (ChIP) analysis indicates that this correlated with reduced promoter occupancy of PPAR / on the Angptl4 and Adrp genes. Reporter assays demonstrated antagonism of PPAR / activity and weak antagonism and agonism of PPAR activity but no effect on PPAR activity. Time-resolved fluorescence resonance energy transfer assays confirmed the ability of GSK3787 to modulate the association of both PPAR / and PPAR 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 PPAR activity is markedly lower than the efficacy of GSK3787 to act as a PPAR / 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 PPAR / 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.