Discovery of a Novel Class of PROTACs as Potent and Selective Estrogen Receptor alpha Degraders to Overcome Endocrine-Resistant Breast Cancer In Vitro and In Vivo

The estrogen receptor (ER) is a well-established target for endocrine therapies of ER-positive breast cancer (ER+ BC), but endocrine resistance limits the efficacy of clinical drugs. Using proteolysis targeting chimera (PROTAC) technology to degrade ER alpha may be an effective alternative to endocrine therapies. Herein, we disclose a novel series of potent and selective ER alpha PROTACs based on an oxabicycloheptane sulfonamide (OBHSA) scaffold, with no associated ER beta degradation. These PROTACs showed significant antiproliferation and ER alpha degradation activities against a broad spectrum of ER+ BC cells including tamoxifen-resistant and ER alpha mutant cell lines. Genomics analysis confirmed that these PROTACs inhibited the nascent RNA synthesis of ER alpha target genes and impaired genome-wide ER alpha binding. Compound ZD12 exhibited excellent antitumor potency and ER alpha degradation activity in both tamoxifen-sensitive and-resistant BC mice models, which are superior to fulvestrant. This study demonstrates the potential of these PROTACs as novel drug candidates for endocrine-resistant BC treatment.

Automated summary

This study reveals a novel series of potent ER alpha PROTACs based on the OBHSA scaffold, showing significant antiproliferation and ER alpha degradation activities against a broad spectrum of ER+ BC cells. Compound ZD12 exhibits excellent antitumor potency and ER alpha degradation activity, making it a promising drug candidate for endocrine-resistant BC treatment.