Abstract 4510: Potent and orally efficacious PROTAC degraders of estrogen receptor α (ERα)

Abstract The estrogen receptor α (ERα) plays a crucial role in hormonally driven breast cancer, making it a clinically validated oncology target. Over the past 30 years, SERMs, SERDs, and AIs have been the mainstay of endocrine therapy for ER+ breast cancer, but relapse and resistance remains a significant challenge for metastatic breast cancer, leading to cancer recurrences, metastasis, and mortality. We report the discovery and extensive evaluations of potent and orally efficacious ERα degraders using the PROTAC technology through extensive optimization of the cereblon ligands, the linker and ER ligands. Our lead compounds (UM-ERD-3111 and UM-ERD-4001) achieved sub-nanomlar DC50 values in ER degradation and demonstrate excellent oral bioavailability. Oral administration of these ER degraders effectively reduces the ER wild-type and ER mutated proteins in tumor tissues in mice. Both ERD-3111 and UM-ERD-4001 are capable of inducing tumor regression in vivo and are more efficacious than ARV-471, a PROTAC ER degrader currently in phase 3 clinical development. UM-ERD-3111 and UM-ERD-4001 are highly promising compounds for extensive evaluations as potential new therapies for the treatment of ER+ human breast cancer. Citation Format: Rohan K. Rej, Zhixiang Chen, Ranjan K. Acharyya, Dimin Wu, Biao Hu, Guozhang Xu, Rakesh Nagilla, Hoda Metwally, Yu Wang, Bo Wen, Duxin Sun, Longchuan Bai, Shaomeng Wang. Potent and orally efficacious PROTAC degraders of estrogen receptor α (ERα) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4510.