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

作者：Jain Disha; Koh John T^*

来源：Bioorganic & Medicinal Chemistry Letters, 2010, 20(17): 5258-5261.

DOI：10.1016/j.bmcl.2010.06.151

• Estrogen receptor
• Estrogen response element
• AP-1
• SERM

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 ER beta agonists/partial agonists on AP-1 responsive genes. While developing a mutant selective analog of Raloxifene, that is an antagonist of ER alpha(E353A), we discovered an antagonist of wild-type ER alpha and ER beta that is also an antagonist of ER beta/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.

• 出版日期2010-9-1