化学
雌激素受体
乳腺癌
癌症
雌激素
人体乳房
药理学
口服活性
内科学
癌症研究
医学
体外
生物化学
作者
Ranjan Kumar Acharyya,Rohan Kalyan Rej,Biao Hu,Zhixiang Chen,Dimin Wu,Jianfeng Lü,Hoda Metwally,Donna McEachern,Yu Wang,Wei Jiang,Longchuan Bai,Jelena Tošović,Christina L. Gersch,Guozhang Xu,Weihong Zhang,Wenxue Wu,E. Scott Priestley,Zhihua Sui,Farzad Sarkari,Bo Wen,Duxin Sun,James M. Rae,Shaomeng Wang
标识
DOI:10.1021/acs.jmedchem.4c01521
摘要
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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