Discovery of ERD-12310A as an Exceptionally Potent and Orally Efficacious PROTAC Degrader of Estrogen Receptor α (ERα)
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 DC<sub>50</sub> 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 <i>ESR1</i><sup>Y537S</sup> 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.
Authors
- Meilin Wang (ORCID: https://orcid.org/0000-0003-4509-9561)
- Ranjan Kumar Acharyya (ORCID: https://orcid.org/0000-0002-1562-0216)
- Biao Hu (ORCID: https://orcid.org/0000-0002-4691-6490)
- Rohan Kalyan Rej (ORCID: https://orcid.org/0000-0003-0904-9137)
- E. Scott Priestley (ORCID: https://orcid.org/0000-0001-8390-1143)
- Wei Jiang (ORCID: https://orcid.org/0000-0002-5306-1398)
- Hoda Metwally
- Bo Wen (ORCID: https://orcid.org/0000-0002-8337-220X)
- Longchuan Bai (ORCID: https://orcid.org/0000-0003-1025-2925)
- James M. Rae (ORCID: https://orcid.org/0000-0002-3412-8219)
- John A. Katzenellenbogen (ORCID: https://orcid.org/0000-0003-0914-0010)
- Donna McEachern (ORCID: https://orcid.org/0000-0001-8662-3425)
- Kathryn E. Carlson (ORCID: https://orcid.org/0000-0002-1449-9645)
- Christina L. Gersch (ORCID: https://orcid.org/0000-0001-7381-6703)
- Duxin Sun (ORCID: https://orcid.org/0000-0002-6406-2126)
- Shaomeng Wang (ORCID: https://orcid.org/0000-0002-8782-6950)
- Wenxue Wu (ORCID: https://orcid.org/0000-0002-5979-9350)
- Yu Wang (ORCID: https://orcid.org/0000-0002-6608-4310)
- Weihong Zhang (ORCID: https://orcid.org/0000-0001-8997-3092)
- Zhixiang Chen (ORCID: https://orcid.org/0009-0007-4526-1588)
- Guozhang Xu (ORCID: https://orcid.org/0000-0002-2346-3732)
- Zhihua Sui
- Dimin Wu
- Leticia S Nishimura
Institutions
- University of Illinois Urbana-Champaign (US)
- University of Michigan (US)
- SK Life Science (United States) (US)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-11-25
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c01401
- Citations
- 17
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 3.97
Funders
- Breast Cancer Research Foundation
- SK Life Science
- Roivant Sciences
- Center for Scientific Review