雌激素受体α (ERα) 是治疗ER阳性 (ER+) 乳腺癌的主要靶点。尽管已经发展出多种有效的针对ERα信号传导的治疗方法，但临床耐药仍然是一个重要挑战。在本研究中，我们报告了使用PROTAC技术发现了一类新的具有强效和口服生物利用度的ERα降解剂，其中ERD-3111是最具有潜力的化合物。ERD-3111在体外对ERα表现出强效的降解活性，并在小鼠、大鼠和狗中显示出高生物利用度。口服给予ERD-3111有效地降低了肿瘤组织中野生型和突变型ERα蛋白的水平。ERD-3111在野生型ER和两个临床相关的ESR1突变模型的MCF-7母体异种移植模型中实现了肿瘤回归或完全抑制生长的效果。ERD-3111是一种有希望的用于进一步广泛评估治疗ER+乳腺癌的ERα降解剂。

Estrogen receptor α (ERα) is a prime target for the treatment of ER-positive (ER+) breast cancer. Despite the development of several effective therapies targeting ERα signaling, clinical resistance remains a major challenge. In this study, we report the discovery of a new class of potent and orally bioavailable ERα degraders using the PROTAC technology, with ERD-3111 being the most promising compound. ERD-3111 exhibits potent in vitro degradation activity against ERα and demonstrates high oral bioavailability in mice, rats, and dogs. Oral administration of ERD-3111 effectively reduces the levels of wild-type and mutated ERα proteins in tumor tissues. ERD-3111 achieves tumor regression or complete tumor growth inhibition in the parental MCF-7 xenograft model with wild-type ER and two clinically relevant ESR1 mutated models in mice. ERD-3111 is a promising ERα degrader for further extensive evaluations for the treatment of ER+ breast cancer.