Identification of Bexarotene as a PPAR γ 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),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. © 2015 david p. marciano et al.