Identification of Bexarotene as a PPAR [gamma] 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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Bibliographic Details
Published in:PPAR research 2015-01, Vol.2015
Main Authors: Marciano, David P, Kuruvilla, Dana S, Pascal, Bruce D, Griffin, Patrick R
Format: Article
Language:English
Subjects:
Alzheimer's disease
Automation
Competition
Gene expression
Insulin resistance
Kinases
Ligands
Metabolic disorders
Peptides
Proteins
Regulatory approval
Rodents
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Summary: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.
ISSN:1687-4757
1687-4765
DOI:10.1155/2015/254560