From Pure Antagonists to Pure Degraders of the Estrogen Receptor: Evolving Strategies for the Same Target

[Image: see text] Pure antiestrogens, or selective estrogen receptor degraders (SERDs), have proven to be effective in treating breast cancer that has progressed on tamoxifen and/or aromatase inhibitors. However, the only FDA-approved pure antiestrogen, fulvestrant, is limited in efficacy by its low bioavailability. The search for orally bioavailable SERDs has continued for nearly as long as the clinical history of the injection-only fulvestrant. Oral SERDs that have been developed and tested in patients ranged from nonsteroidal ER binders containing an acrylic acid or amino side chain to bifunctional proteolysis-targeting chimera (PROTAC) pure ER degraders. Structural evolution in the development of oral SERD molecules has been closely associated with quantifiable ER-degrading potency, as seen in the structural comparison analysis of acrylic acid and basic amino side-chain-bearing SERDs. Failure to improve on fulvestrant in the clinical trials by numerous acidic SERDs and early basic SERDs is blamed on tolerability and/or insufficient efficacy, which will likely be overcome by the new-generation basic SERD molecules and PROTAC ER degraders with improved oral bioavailability, low toxicity, and superior efficacy of receptor degradation.