An Estrogen Receptor β Agonist with AR Antagonist Activity from a Modern Asymmetric <i>De Novo</i> Steroid Synthesis

While the androgen receptor (AR) has long been a molecular target of prostate cancer therapeutics, the estrogen receptor β (ERβ) has more recently become of interest in this area of chemotherapeutic space due to its demonstrated role as a tumor suppressor. Here, we report studies that build on our earlier discovery of an exquisitely potent and selective steroidal agonist of ERβ that have resulted in the identification of a synthetic substituted estrane that, in reporter assays, is a potent and selective agonist of ERβ over ERα while also possessing activity as an antagonist of the AR that has potency within 7-fold of enzalutamide. Notably, this discovery was made possible by leveraging the power of our modern asymmetric <i>de novo</i> chemical synthesis of estranes that obviates the typical dependence on semisynthesis (natural product derivatization) for steroid-based medicinal chemistry.