Discovery of ERD-1233 as a Potent and Orally Efficacious Estrogen Receptor PROTAC Degrader for the Treatment of ER+ Human Breast Cancer

  • J Med Chem. 2024 Nov 14;67(21):19010-19037. doi: 10.1021/acs.jmedchem.4c01521.
Ranjan Kumar Acharyya  1 ,  Rohan Kalyan Rej  1 ,  Biao Hu  1 ,  Zhixiang Chen  1 ,  Dimin Wu  1 ,  Jianfeng Lu  1 ,  Hoda Metwally  1 ,  Donna McEachern  1 ,  Yu Wang  1 ,  Wei Jiang  1 ,  Longchuan Bai  1 ,  Jelena Tošović  1 ,  Christina L Gersch  1 ,  Guozhang Xu  2 ,  Weihong Zhang  2 ,  WenXue Wu  2 ,  E Scott Priestley  2 ,  Zhihua Sui  2 ,  Farzad Sarkari  3 ,  Bo Wen  3 ,  Duxin Sun  3 ,  James M Rae  1  4  5 ,  Shaomeng Wang  1  4  6  5
Affiliations
  • 1. Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 2. SK Life Science Laboratories, 2500 Renaissance Blvd, King of Prussia, Pennsylvania 19406, United States.
  • 3. Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 4. Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 5. The Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 6. Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States.
PMID: 39485242 DOI: 10.1021/acs.jmedchem.4c01521
Abstract

Despite the development of highly effective therapies for the treatment of Estrogen Receptor α (ERα)-positive human Breast Cancer, clinical resistance to current therapies requires the development of novel therapeutic strategies. Herein, we report the discovery of ERD-1233 as a potent and orally efficacious ERα Degrader designed using the PROTAC technology. ERD-1233 was developed based on Lasofoxifene as the ER binding moiety and a novel Cereblon Ligand through extensive optimization of the linker. ERD-1233 potently and effectively reduces the ERα protein in vitro and achieves excellent oral bioavailability in mice and rats. Oral administration of ERD-1233 effectively reduces ER protein in ER+ Tumors and achieves tumor regression in the ER wild-type MCF-7 xenograft tumor model and strong tumor growth inhibition in the ESR1Y537S mutated model in mice. Our data demonstrate that ERD-1233 is a promising ER PROTAC degrader for extensive evaluation as a new therapy for the treatment of ER+ human Breast Cancer.

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