Abstract
Peroxisome proliferator-activated receptor β/δ (PPARβ/δ) is a ligand-regulated nuclear receptor with essential functions in metabolism and inflammation. We have synthesized a new derivative [methyl 3-(N-(4-(hexylamino)-2-methoxyphenyl)sulfamoyl)thiophene-2-carboxylate (ST247) structurally related to the published PPARβ/δ inhibitory ligand methyl 3-(N-(2-methoxy-4-(phenylamino)phenyl)sulfamoyl)thiophene-2-carboxylate (GSK0660). ST247 has a higher affinity to PPARβ/δ than GSK0660, and at equimolar concentrations, it more efficiently 1) induces the interaction with corepressors both in vitro and in vivo, 2) inhibits the agonist-induced transcriptional activity of PPARβ/δ, and 3) down-regulates basal level expression of the peroxisome proliferator responsive element-driven PPARβ/δ target gene ANGPTL4. Methyl 3-(N-(4-(tert-butylamino)-2-methoxyphenyl)sulfamoyl)thiophene-2-carboxylate (PT-S58), another high-affinity derivative from our series, also efficiently inhibits agonist-induced transcriptional activation, but in contrast to ST247, it does not enhance the interaction of PPARβ/δ with corepressors. PT-S58 rather prevents corepressor recruitment triggered by the inverse agonist ST247. These findings classify ST247 as an inverse agonist, whereas PT-S58 is the first pure PPARβ/δ antagonist described to date. It is noteworthy that ST247 and PT-S58 are also effective on PPRE-independent functions of PPARβ/δ: in monocytic cells, both ligands modulate expression of the activation marker CCL2 in the opposite direction as an established PPARβ/δ agonist. The possibility to differentially modulate specific functions of PPARβ/δ makes these novel compounds invaluable tools to advance our understanding of PPARβ/δ biology.
Footnotes
This work is supported by the Deutsche Forschungsgemeinschaft [Grant SFB-TR17/A3]; and the LOEWE-Schwerpunkt “Tumor and Inflammation” of the state of Hesse.
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
doi:10.1124/mol.111.074039.
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ABBREVIATIONS:
- PPAR
- peroxisome proliferator-activated receptor
- PPRE
- peroxisome proliferator response element
- SMRT
- silencing mediator of retinoic and thyroid hormone
- Bcl-6
- B-cell lymphoma 6
- DMEM
- Dulbecco's minimal essential medium
- GSK3787
- 4-chloro-N-(2-((5-trifluoromethyl-2-pyridyl)sulfonyl)ethyl)benzamide
- GSK0660
- methyl 3-(N-(2-methoxy-4-(phenylamino)phenyl)sulfamoyl)thiophene-2-carboxylate
- GW501516
- [2-methyl-4-[[[4-methyl-2-[4-(trifluoromethyl)phenyl]-5-thiazolyl]methyl]thio]phenoxy]-acetic acid
- GW1929
- N-(2-benzoylphenyl)-O-[2-(methyl-2-pyridinylamino)ethyl]-l-tyrosine hydrochloride
- GW7647
- 2-(4-(2-(1-cyclohexanebutyl)-3-cyclohexylureido)ethyl)-phenyl-thio)-2-methyl-propionic acid
- M-CSF
- macrophage–colony-stimulating factor
- PBS
- phosphate-buffered saline
- TGM
- thioglycollate-elicited macrophages
- RT-qPCR
- real-time quantitative polymerase chain reaction
- ChIP
- chromatin immunoprecipitation
- HDAC3
- α-histone deacetylase 3
- TR-FRET
- time-resolved fluorescence resonance energy transfer
- ID2
- interaction domain 2
- LBD
- ligand binding domain
- DMSO
- dimethyl sulfoxide
- GST
- glutathione transferase
- Angptl4
- angiopoietin-like 4
- PT-S58
- methyl 3-(N-(4-(tert-butylamino)-2-methoxyphenyl)sulfamoyl)thiophene-2-carboxylate
- ST247
- methyl 3-(N-(4-(hexylamino)-2-methoxyphenyl)sulfamoyl)thiophene-2-carboxylate.
- Received June 9, 2011.
- Accepted August 23, 2011.
- Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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