标题:通过 PROTAC 降解雌激素受体 α:克服内分泌耐药性的有前途方法
Title:Targeting estrogen receptor α for degradation with PROTACs: A promising approach to overcome endocrine resistance
作者:Lin X 等人
发表期刊:European Journal of Medicinal Chemistry (《欧洲药物化学杂志》)
出版年份:2020
1. 研究背景 /
雌激素受体α(ERα)是乳腺癌治疗中的重要靶点。然而,由于长期使用内分泌疗法(例如选择性雌激素受体调节剂 SERM 和芳香化酶抑制剂)可能导致 ERα 依赖性机制的耐药性,这显著限制了治疗效果。
Research Background
Estrogen receptor alpha (ERα) plays a critical role in the treatment of breast cancer. However, prolonged use of endocrine therapies such as selective estrogen receptor modulators (SERMs) and aromatase inhibitors often leads to ERα-dependent resistance mechanisms, significantly limiting their effectiveness.
2. 研究目标
研究旨在利用 PROTAC 技术(蛋白降解靶向嵌合体)设计并优化针对 ERα 的降解剂,以克服乳腺癌内分泌耐药性。
Research Objective
The study aims to develop and optimize PROTACs (Proteolysis Targeting Chimeras) to selectively degrade ERα, overcoming endocrine resistance in breast cancer.
3. 研究方法
- 合成了多个候选 PROTAC 分子,通过化学连接小分子配体(与 ERα 结合)和泛素连接酶配体(CRBN 或 VHL)设计而成。
- 在体外和细胞模型中,通过 Western blot 和降解曲线测试其降解效率。
- 评估这些化合物对乳腺癌细胞增殖的抑制作用,以及选择性毒性。
Methods
- A series of candidate PROTACs were synthesized by chemically linking small molecule ligands (targeting ERα) with ubiquitin ligase ligands (e.g., CRBN or VHL).
- Degradation efficiency was tested in vitro and in cellular models using Western blot and degradation curves.
- The compounds were evaluated for their anti-proliferative effects on breast cancer cells and their selective toxicity.
4. 主要发现
- PROTAC 分子在低浓度(nM 范围)下即可实现对 ERα 的高效降解,表现出比传统 ERα 抑制剂更高的选择性。
- 部分 PROTAC 对乳腺癌细胞(包括耐药性细胞系)具有显著的抗肿瘤活性。
- 这些化合物显示出良好的成药潜力,为乳腺癌耐药治疗提供了新策略。
Key Findings
- The PROTAC molecules effectively degraded ERα at low concentrations (in the nanomolar range), showing higher selectivity than traditional ERα inhibitors.
- Some PROTACs exhibited significant anti-tumor activity in breast cancer cells, including resistant cell lines.
- These compounds demonstrated promising drug-like properties, offering a novel strategy for overcoming breast cancer resistance.
5. 研究意义
PROTAC 技术为克服内分泌治疗耐药性提供了全新的治疗策略,可能成为未来乳腺癌治疗的重要手段。文章为后续研究提供了基础,并指出了未来在 PROTAC 药物开发中的挑战和方向。
Significance
The study highlights PROTAC technology as a novel therapeutic strategy to overcome endocrine resistance, potentially transforming breast cancer treatment. It lays the foundation for future studies and discusses challenges and directions in PROTAC drug development.