Discovery of ERD-308 as a Highly Potent Proteolysis Targeting Chimera (PROTAC) Degrader of Estrogen Receptor (ER)

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 DC50 (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（estrogen receptor, ER）是治疗雌激素受体阳性（ER+）乳腺癌的经过验证的靶点。本文阐述了基于蛋白水解靶向嵌合体（proteolysis targeting chimeras, PROTAC）理念设计、合成并开展全面构效关系（structure–activity relationship, SAR）研究的小分子ERα降解剂。本研究发现了活性优异且高效的PROTAC类ER降解剂，以ERD-308（32）为例。ERD-308在MCF-7和T47D这两种ER+乳腺癌细胞系中，半数降解浓度（DC50，即引发50%蛋白质降解的浓度）分别为0.17 nM和0.43 nM，且在低至5 nM的浓度下即可在两种细胞系中诱导超过95%的ER降解。值得注意的是，ERD-308相较于氟维司群——目前唯一获批的选择性ER降解剂（selective ER degrader, SERD）——能诱导更完全的ER降解，且在MCF-7细胞中抑制细胞增殖的效果优于氟维司群。对ERD-308的进一步优化有望为晚期ER+乳腺癌带来全新的治疗方案。