2. Academic Validation
  3. Discovery of ERD-12310A as an Exceptionally Potent and Orally Efficacious PROTAC Degrader of Estrogen Receptor α (ERα)

Discovery of ERD-12310A as an Exceptionally Potent and Orally Efficacious PROTAC Degrader of Estrogen Receptor α (ERα)

  • J Med Chem. 2024 Dec 12;67(23):20933-20965. doi: 10.1021/acs.jmedchem.4c01401.
Rohan Kalyan Rej 1,  Biao Hu 1,  Zhixiang Chen 1,  Ranjan Kumar Acharyya 1,  Dimin Wu 1,  Hoda Metwally 1,  Donna McEachern 1,  Yu Wang 1,  Wei Jiang 1,  Longchuan Bai 1,  Leticia S Nishimura 1,  Christina L Gersch 1,  Meilin Wang 2,  Bo Wen 2,  Duxin Sun 2 3,  Kathryn Carlson 4,  John A Katzenellenbogen 4,  Guozhang Xu 5,  Weihong Zhang 5,  Wenxue Wu 5,  E Scott Priestley 5,  Zhihua Sui 5,  James M Rae 1 3 6,  Shaomeng Wang 1 3 6 7
Affiliations

Affiliations

  • 1 Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan, Ann Arbor 48109, United States.
  • 2 Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor 48109, United States.
  • 3 Rogel Cancer Center, University of Michigan, Ann Arbor 48109, United States.
  • 4 Department of Chemistry, University of Illinois, 600 South Mathews Avenue, Urbana 61801, United States.
  • 5 SK Life Science Laboratories, 2500 Renaissance Boulevard, King of Prussia 09406, United States.
  • 6 Department of Pharmacology, University of Michigan, Ann Arbor 48109, United States.
  • 7 Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor 48109, United States.
PMID: 39585895 DOI: 10.1021/acs.jmedchem.4c01401
Abstract

Inhibition of Estrogen Receptor alpha (ERα) signaling is an established therapeutic approach for the treatment of ER-positive (ER+) breast cancers, but new therapeutic strategies are urgently needed to overcome clinical resistance. In the present study, we describe the discovery and extensive evaluation of ERD-12310A as an exceptionally potent and orally efficacious PROTAC degrader of ERα. ERD-12310A achieved a DC50 value of 47 pM and is 10 times more potent than ARV-471. ERD-12310A displayed an improved pharmacokinetic profile in mice and rats over ARV-471. ERD-12310A attained tumor regression in the ER+, estrogen-dependent MCF-7 breast Cancer xenograft model with wild-type ER and is more potent than ARV-471. Importantly, ERD-12310A achieved strong tumor growth inhibition in MCF-7 xenograft tumors harboring the clinically relevant ESR1Y537S mutation, which confers resistance to traditional antiestrogens. Our data position ERD-12310A as a promising candidate for further development as a potential therapy for ER+ breast Cancer.

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