title: A mutant selective anti-estrogen is a pure antagonist on EREs and AP-1 response elements.
abstract: Estrogen receptors (ERs) regulate gene transcription through classic estrogen response elements (EREs) as well as AP-1 responsive genes. The common SERMs Raloxifene, Tamoxifen, and ICI164384 function as ER antagonists on EREs but as ERbeta agonists/partial agonists on AP-1 responsive genes. While developing a mutant selective analog of Raloxifene, that is an antagonist of ERalpha(E353A), we discovered an antagonist of wild-type ERalpha and ERbeta that is also an antagonist of ERbeta/AP-1 response. The analog, DRL527, represses basal AP-1 gene expression and antagonizes Raloxifene stimulated AP-1 expression. Therefore DRL527 has a unique, previously unreported, ERE/AP-1 activity profile.
authors.affiliation: Department of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716, USA.
authors.forename: Disha
authors.initials: D
authors.lastname: Jain
authors.forename: John T
authors.initials: JT
authors.lastname: Koh
mesh_terms: D020847:Estrogen Receptor Modulators / Q000494:pharmacology*; D009154:Mutation; D011960:Receptors, Estrogen / Q000235:genetics*; D018808:Transcription Factor AP-1 / Q000235:genetics*
chemical_list: D020847:Estrogen Receptor Modulators; D011960:Receptors, Estrogen; D018808:Transcription Factor AP-1