A mutant selective anti-estrogen is a pure antagonist on EREs and AP-1 response elements.

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. Copyright 2010 Elsevier Ltd. All rights reserved.