Bisphenol A derivatives act as novel coactivator-binding inhibitors for estrogen receptor β

Bisphenol A and its derivatives are recognized as endocrine disruptors based on their complex effects on estrogen receptor (ER) signaling. While the effects of bisphenol derivatives on ER alpha have been thoroughly evaluated, how these chemicals affect ER beta signaling is less well understood. Herein, we sought to identify novel ER beta ligands using a radioligand competitive binding assay to screen a chemical library of bisphenol derivatives. Many of the compounds identified showed intriguing dual activities as both ER alpha agonists and ER beta antagonists. Docking simulations of these compounds and ER beta suggested that they bound not only to the canonical binding site of ER beta but also to the coactivator binding site located on the surface of the receptor, suggesting that they act as coactivator-binding inhibitors (CBIs). Receptor-ligand binding experiments using WT and mutated ER beta support the presence of a second ligand-interaction position at the coactivator-binding site in ER beta, and direct binding experiments of ER beta and a coactivator peptide confirmed that these compounds act as CBIs. Our study is the first to propose that bisphenol derivatives act as CBIs, presenting critical insight for the future development of ER signaling-based drugs and their potential to function as endocrine disruptors.

Automated summary

Bisphenol derivatives were found to act as coactivator-binding inhibitors (CBIs) affecting ERβ signaling, providing critical insights for future drug development based on ER signaling and revealing their potential as endocrine disruptors.