Identification of Bexarotene as a PPARγ Antagonist with HDX
The retinoid x receptors (RXRs) are the pharmacological target of Bexarotene, an antineoplastic agent indicated for the treatment of cutaneous T cell lymphoma (CTCL). The RXRs form heterodimers with several nuclear receptors (NRs), including peroxisome proliferator-activated receptor gamma (PPARγ),...
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| Format: | Article |
| Language: | English |
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Wiley
2015-01-01
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| Series: | PPAR Research |
| Online Access: | http://dx.doi.org/10.1155/2015/254560 |
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| author | David P. Marciano Dana S. Kuruvilla Bruce D. Pascal Patrick R. Griffin |
| author_facet | David P. Marciano Dana S. Kuruvilla Bruce D. Pascal Patrick R. Griffin |
| author_sort | David P. Marciano |
| collection | DOAJ |
| description | The retinoid x receptors (RXRs) are the pharmacological target of Bexarotene, an antineoplastic agent indicated for the treatment of cutaneous T cell lymphoma (CTCL). The RXRs form heterodimers with several nuclear receptors (NRs), including peroxisome proliferator-activated receptor gamma (PPARγ), to regulate target gene expression through cooperative recruitment of transcriptional machinery. Here we have applied hydrogen/deuterium exchange (HDX) mass spectrometry to characterize the effects of Bexarotene on the conformational plasticity of the intact RXRα:PPARγ heterodimer. Interestingly, addition of Bexarotene to PPARγ in the absence of RXRα induced protection from solvent exchange, suggesting direct receptor binding. This observation was confirmed using a competitive binding assay. Furthermore, Bexarotene functioned as a PPARγ antagonist able to alter rosiglitazone induced transactivation in a cell based promoter:reporter transactivation assay. Together these results highlight the complex polypharmacology of lipophilic NR targeted small molecules and the utility of HDX for identifying and characterizing these interactions. |
| format | Article |
| id | doaj-art-2e65e3205c904a3dba4132169fdecb5b |
| institution | Kabale University |
| issn | 1687-4757 1687-4765 |
| language | English |
| publishDate | 2015-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | PPAR Research |
| spelling | doaj-art-2e65e3205c904a3dba4132169fdecb5b2025-02-03T01:12:40ZengWileyPPAR Research1687-47571687-47652015-01-01201510.1155/2015/254560254560Identification of Bexarotene as a PPARγ Antagonist with HDXDavid P. Marciano0Dana S. Kuruvilla1Bruce D. Pascal2Patrick R. Griffin3Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, FL 33458, USADepartment of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, FL 33458, USADepartment of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, FL 33458, USADepartment of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, FL 33458, USAThe retinoid x receptors (RXRs) are the pharmacological target of Bexarotene, an antineoplastic agent indicated for the treatment of cutaneous T cell lymphoma (CTCL). The RXRs form heterodimers with several nuclear receptors (NRs), including peroxisome proliferator-activated receptor gamma (PPARγ), to regulate target gene expression through cooperative recruitment of transcriptional machinery. Here we have applied hydrogen/deuterium exchange (HDX) mass spectrometry to characterize the effects of Bexarotene on the conformational plasticity of the intact RXRα:PPARγ heterodimer. Interestingly, addition of Bexarotene to PPARγ in the absence of RXRα induced protection from solvent exchange, suggesting direct receptor binding. This observation was confirmed using a competitive binding assay. Furthermore, Bexarotene functioned as a PPARγ antagonist able to alter rosiglitazone induced transactivation in a cell based promoter:reporter transactivation assay. Together these results highlight the complex polypharmacology of lipophilic NR targeted small molecules and the utility of HDX for identifying and characterizing these interactions.http://dx.doi.org/10.1155/2015/254560 |
| spellingShingle | David P. Marciano Dana S. Kuruvilla Bruce D. Pascal Patrick R. Griffin Identification of Bexarotene as a PPARγ Antagonist with HDX PPAR Research |
| title | Identification of Bexarotene as a PPARγ Antagonist with HDX |
| title_full | Identification of Bexarotene as a PPARγ Antagonist with HDX |
| title_fullStr | Identification of Bexarotene as a PPARγ Antagonist with HDX |
| title_full_unstemmed | Identification of Bexarotene as a PPARγ Antagonist with HDX |
| title_short | Identification of Bexarotene as a PPARγ Antagonist with HDX |
| title_sort | identification of bexarotene as a pparγ antagonist with hdx |
| url | http://dx.doi.org/10.1155/2015/254560 |
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