Discovery of <b>ERD-3111</b> as a Potent and Orally Efficacious Estrogen Receptor PROTAC Degrader with Strong Antitumor Activity
Zhixiang Chen, Biao Hu, Rohan Kalyan Rej, Dimin Wu, Ranjan Kumar Acharyya, Mingliang Wang, Tianfeng Xu, Jianfeng Lü, Hoda Metwally, Yu Wang, Donna McEachern, Longchuan Bai, Christina L. Gersch, Meilin Wang, Wenjing Zhang, Qiuxia Li, Bo Wen, Duxin Sun, James M. Rae, Shaomeng Wang
Abstract
Estrogen receptor α (ERα) is a prime target for the treatment of ER-positive (ER+) breast cancer. Despite the development of several effective therapies targeting ERα signaling, clinical resistance remains a major challenge. In this study, we report the discovery of a new class of potent and orally bioavailable ERα degraders using the PROTAC technology, with ERD-3111 being the most promising compound. ERD-3111 exhibits potent in vitro degradation activity against ERα and demonstrates high oral bioavailability in mice, rats, and dogs. Oral administration of ERD-3111 effectively reduces the levels of wild-type and mutated ERα proteins in tumor tissues. ERD-3111 achieves tumor regression or complete tumor growth inhibition in the parental MCF-7 xenograft model with wild-type ER and two clinically relevant ESR1 mutated models in mice. ERD-3111 is a promising ERα degrader for further extensive evaluations for the treatment of ER+ breast cancer.