Identification of Novel ERβ Ligands ^†

Abstract

The estrogen receptor (ER) is a major therapeutic target in treating estrogen-related diseases, such as breast cancer. There is a need to develop potent ER ligands capable of selectively targeting cancer cells without affecting normal cells. Blocking ERα action by antagonists and inhibiting steroidogenic enzymes has been standard therapy in breast cancer treatment for many years. On the other hand, the ERβ isoform usually has antiproliferative and tumor-suppressive functions, so targeting ERβ with specific agonists represents a promising new approach not only in breast cancer but also in prostate cancer therapy. Besides the anticancer activity of ERβ agonists, their application is considered in treating depression, anxiety, and inflammation. To obtain potent antiproliferative agents, a triazole ring is often incorporated as a pharmacophore in the steroid skeleton. This study evaluates the binding affinity of novel N(2)-substituted D-condensed steroidal triazoles for ligand-binding domains (LBDs) of ERβ and androgen receptors using a yeast-based fluorescent assay. The LBD of the steroid receptor was expressed in-frame with a yellow fluorescent protein (YFP) in Saccharomyces cerevisiae. Upon ligand-binding induced dimerization, fluorescence resonance energy transfer (FRET) between YFP molecules was analyzed using fluorescence spectroscopy and microscopy. We identified new selective ERβ ligands without androgenic properties, but further experiments are required to determine whether their mechanism of action is agonistic or antagonistic. Considering the broad therapeutic potential of specific ERβ ligands, our findings indicate that steroid derivatives containing triazole are promising bioactive compounds in the field of anticancer agents.