TY - JOUR
T1 - Discovery of ERD-12310A as an Exceptionally Potent and Orally Efficacious PROTAC Degrader of Estrogen Receptor α (ERα)
AU - Rej, Rohan Kalyan
AU - Hu, Biao
AU - Chen, Zhixiang
AU - Acharyya, Ranjan Kumar
AU - Wu, Dimin
AU - Metwally, Hoda
AU - McEachern, Donna
AU - Wang, Yu
AU - Jiang, Wei
AU - Bai, Longchuan
AU - Nishimura, Leticia S.
AU - Gersch, Christina L.
AU - Wang, Meilin
AU - Wen, Bo
AU - Sun, Duxin
AU - Carlson, Kathryn
AU - Katzenellenbogen, John A.
AU - Xu, Guozhang
AU - Zhang, Weihong
AU - Wu, Wenxue
AU - Priestley, E. Scott
AU - Sui, Zhihua
AU - Rae, James M.
AU - Wang, Shaomeng
N1 - This study was supported by funding from Oncopia Therapeutics, Inc., Proteovant Therapeutics, Inc., the Breast Cancer Research Foundation (BCRF) (J.M.R.) and the University of Michigan Comprehensive Cancer Center Core Grant from the National Cancer Institute, NIH (P30CA046592).
PY - 2024/12/12
Y1 - 2024/12/12
N2 - 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.
AB - 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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U2 - 10.1021/acs.jmedchem.4c01401
DO - 10.1021/acs.jmedchem.4c01401
M3 - Article
C2 - 39585895
AN - SCOPUS:85210295868
SN - 0022-2623
VL - 67
SP - 20933
EP - 20965
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 23
ER -