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

Rohan Kalyan Rej; Biao Hu; Zhixiang Chen; Ranjan Kumar Acharyya; Dimin Wu; Hoda Metwally; Donna McEachern; Yu Wang; Wei Jiang; Longchuan Bai; Leticia S Nishimura; Christina L Gersch; Meilin Wang; Bo Wen; Duxin Sun; Kathryn Carlson; John A Katzenellenbogen; Guozhang Xu; Weihong Zhang; Wenxue Wu; E Scott Priestley; Zhihua Sui; James M Rae; Shaomeng Wang

doi:10.1021/acs.jmedchem.4c01401

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

J Med Chem. 2024 Nov 25. doi: 10.1021/acs.jmedchem.4c01401. Online ahead of print.

Authors

Rohan Kalyan Rej¹, Biao Hu¹, Zhixiang Chen¹, Ranjan Kumar Acharyya¹, Dimin Wu¹, Hoda Metwally¹, Donna McEachern¹, Yu Wang¹, Wei Jiang¹, Longchuan Bai¹, Leticia S Nishimura¹, Christina L Gersch¹, Meilin Wang², Bo Wen², Duxin Sun^{2

3}, Kathryn Carlson⁴, John A Katzenellenbogen⁴, Guozhang Xu⁵, Weihong Zhang⁵, Wenxue Wu⁵, E Scott Priestley⁵, Zhihua Sui⁵, James M Rae^{1

3

6}, Shaomeng Wang^{1

3

6

7}

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 ESR1^Y537S 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.