An Estrogen Receptor β Agonist with AR Antagonist Activity from a Modern Asymmetric De Novo 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 de novo chemical synthesis of estranes that obviates the typical dependence on semisynthesis (natural product derivatization) for steroid-based medicinal chemistry.