Discovery of ERD-3111 as a Potent and Orally Efficacious Estrogen Receptor PROTAC Degrader with Strong Antitumor Activity

  • J Med Chem. 2023 Sep 14;66(17):12559-12585. doi: 10.1021/acs.jmedchem.3c01186.
Zhixiang Chen  1 ,  Biao Hu  1 ,  Rohan Kalyan Rej  1 ,  Dimin Wu  1 ,  Ranjan Kumar Acharyya  1 ,  Mingliang Wang  1 ,  Tianfeng Xu  1 ,  Jianfeng Lu  1 ,  Hoda Metwally  1 ,  Yu Wang  1 ,  Donna McEachern  1 ,  Longchuan Bai  1 ,  Christina L Gersch  1 ,  Meilin Wang  2 ,  Wenjing Zhang  2 ,  Qiuxia Li  2 ,  Bo Wen  2 ,  Duxin Sun  2 ,  James M Rae  1  3  4 ,  Shaomeng Wang  1  3  5  4
Affiliations
  • 1. Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 2. Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 3. Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 4. The Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 5. Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States.
PMID: 37647546 DOI: 10.1021/acs.jmedchem.3c01186
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.

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