富维斯特朗
三苯氧胺
雌激素受体
化学
药理学
雌激素受体α
体内
药物发现
癌症研究
乳腺癌
癌症
生物
内科学
生物化学
医学
遗传学
作者
Baohua Xie,Zhenggang Yin,Zhigang Hu,Lv JunHui,Chuanqian Du,Xiangping Deng,Yuan Huang,Qiuzi Li,Jian Huang,Kaiwei Liang,Hai-Bing Zhou,Chune Dong
标识
DOI:10.1021/acs.jmedchem.2c02032
摘要
The estrogen receptor (ER) is a well-established target for endocrine therapies of ER-positive breast cancer (ER+ BC), but endocrine resistance limits the efficacy of clinical drugs. Using proteolysis targeting chimera (PROTAC) technology to degrade ERα may be an effective alternative to endocrine therapies. Herein, we disclose a novel series of potent and selective ERα PROTACs based on an oxabicycloheptane sulfonamide (OBHSA) scaffold, with no associated ERβ degradation. These PROTACs showed significant antiproliferation and ERα degradation activities against a broad spectrum of ER+ BC cells including tamoxifen-resistant and ERα mutant cell lines. Genomics analysis confirmed that these PROTACs inhibited the nascent RNA synthesis of ERα target genes and impaired genome-wide ERα binding. Compound ZD12 exhibited excellent antitumor potency and ERα degradation activity in both tamoxifen-sensitive and -resistant BC mice models, which are superior to fulvestrant. This study demonstrates the potential of these PROTACs as novel drug candidates for endocrine-resistant BC treatment.
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