Highly potent and selective degrader targeting ERα to improve the treatment outcomes of breast cancer

IF 5.9 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry Pub Date : 2025-09-27 DOI:10.1016/j.ejmech.2025.118199

Xueting Bao , Xunkai Yin , Jinjing Xu , ZhenZhen Zhu , Wenyu Lu , Yihui Cai , Rupeng Dai , Zhe Zheng , Wenzhuo Xu , Shulan Mei , Songyun Xu , Jie Li , Nianguang Li , Haohao Zhu , Jianing Wang , Jian Liu

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Abstract

Estrogen receptor alpha (ERα) is overexpressed in approximately 70 % of breast cancer cases; therefore, it is considered a primary therapeutic target for breast cancer. Several therapeutic agents, including selective estrogen receptor modulators, aromatase inhibitors, selective estrogen receptor degraders, and proteolysis-targeting chimeras (PROTACs), have been developed to antagonize and degrade ERα. The representative ERα-targeting PROTAC (ERα-PROTAC) agent ARV-471 has been used to treat locally advanced or metastatic breast cancer in clinical trials. Herein, we designed, synthesized, and evaluated several novel ERα-PROTAC agents. After systematic structural optimization, compound A16 was found to have excellent antiproliferative and ERα-inhibitory activities in the breast cancer cell line MCF-7. A16 selectively degraded ERα (DC₅₀ = 3.78 nM) through the ubiquitin–proteasome pathway in a time- and concentration-dependent manner. It effectively attenuated drug resistance (MCF-7 Y537S cells; IC₅₀ = 1.3 nM), inhibited proliferation, and induced apoptosis in MCF-7 cells. In addition, it exhibited excellent antitumor effects (10 mg/kg/d intraperitoneal injection; total growth inhibition = 80.11 %) and a good safety profile in an MCF-7 xenograft model, highlighting its potential as a novel drug candidate for breast cancer.

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靶向ERα的高效选择性降解剂改善乳腺癌治疗效果

雌激素受体α (ERα)在大约70%的乳腺癌病例中过度表达；因此，它被认为是乳腺癌的主要治疗靶点。一些治疗药物，包括选择性雌激素受体调节剂、芳香酶抑制剂、选择性雌激素受体降解剂和靶向蛋白水解嵌合体（PROTACs），已经被开发出来对抗和降解ERα。具有代表性的er α靶向PROTAC （ERα-PROTAC）药物ARV-471已在临床试验中用于治疗局部晚期或转移性乳腺癌。在此，我们设计、合成并评价了几种新的ERα-PROTAC药物。经过系统的结构优化，发现化合物A16对乳腺癌细胞系MCF-7具有良好的抗增殖和er α-抑制活性。A16通过泛素-蛋白酶体途径选择性降解ERα (DC50 = 3.78 nM)，且具有时间和浓度依赖性。有效降低MCF-7 Y537S细胞耐药，IC50 = 1.3 nM，抑制MCF-7细胞增殖，诱导细胞凋亡。此外，它还具有出色的抗肿瘤作用（10 mg/kg/d腹腔注射，总生长抑制率为80.11%），并且在MCF-7异种移植模型中具有良好的安全性，突出了其作为乳腺癌新型候选药物的潜力。

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来源期刊

European Journal of Medicinal Chemistry 化学-医药化学

CiteScore

11.70

自引率

9.00%

发文量

863

审稿时长

29 days

期刊介绍： The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers. A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.