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

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

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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