J Med Chem. 2019 Feb 14;62(3):1420-1442. doi: 10.1021/acs.jmedchem.8b01572. Epub 2019 Jan 18.
The estrogen receptor (ER) is a validated target for the treatment of estrogen receptor-positive (ER+) breast cancer. Here, we describe the design, synthesis, and extensive structure-activity relationship (SAR) studies of small-molecule ERα degraders based on the proteolysis targeting chimeras (PROTAC) concept. Our efforts have resulted in the discovery of highly potent and effective PROTAC ER degraders, as exemplified by ERD-308 (32). ERD-308 achieves DC (concentration causing 50% of protein degradation) values of 0.17 and 0.43 nM in MCF-7 and T47D ER+ breast cancer cell lines, respectively, and induces >95% of ER degradation at concentrations as low as 5 nM in both cell lines. Significantly, ERD-308 induces more complete ER degradation than fulvestrant, the only approved selective ER degrader (SERD), and is more effective in inhibition of cell proliferation than fulvestrant in MCF-7 cells. Further optimization of ERD-308 may lead to a new therapy for advanced ER+ breast cancer.
雌激素受体（ER）是治疗雌激素受体阳性（ER+）乳腺癌的有效靶点。在这里，我们描述了基于蛋白水解靶向嵌合体（PROTAC）概念的小分子 ERα 降解剂的设计、合成和广泛的结构-活性关系（SAR）研究。我们的努力发现了高效且有效的 PROTAC ER 降解剂，例如 ERD-308（32）。ERD-308 在 MCF-7 和 T47D ER+乳腺癌细胞系中的 DC（引起 50%蛋白降解的浓度）值分别为 0.17 和 0.43 nM，并在这两种细胞系中浓度低至 5 nM 时即可诱导超过 95%的 ER 降解。值得注意的是，ERD-308 诱导的 ER 降解比唯一批准的选择性 ER 降解剂（SERD）氟维司群更完全，并且在 MCF-7 细胞中比氟维司群更有效地抑制细胞增殖。进一步优化 ERD-308 可能为晚期 ER+乳腺癌提供一种新的治疗方法。
