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Discovery of ERD-3111 as a Potent and Orally Efficacious Estrogen Receptor PROTAC Degrader with Strong Antitumor Activity. 2023
Zhixiang Chen, and
Biao Hu, and
Rohan Kalyan Rej, and
Dimin Wu, and
Ranjan Kumar Acharyya, and
Mingliang Wang, and
Tianfeng Xu, and
Jianfeng Lu, and
Hoda Metwally, and
Yu Wang, and
Donna McEachern, and
Longchuan Bai, and
Christina L Gersch, and
Meilin Wang, and
Wenjing Zhang, and
Qiuxia Li, and
Bo Wen, and
Duxin Sun, and
James M Rae, and
Shaomeng Wang
Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan, Ann Arbor, Michigan 48109, United States.
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.
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