Abstract 7021: Discovery of a highly potent and orally bioavailable ER PROTAC degrader for the treatment of breast cancer

Abstract Breast cancer is the most prevalent invasive cancer among women globally and approximately 70-80% of newly diagnosed breast cancer cases are ER-positive (ER+). Estrogen receptor α (ERα) is a prime target for the treatment of ER+ breast cancer. Despite the development of several effective therapies targeting ERα signaling, clinical resistance remains a major challenge. A promising therapeutic strategy to overcome endocrine resistance in ER+ breast cancer is the development of ER degraders using the proteolysis targeting chimera (PROTAC) technology. Facilitated by our new cereblon ligand library, we have discovered a potent and orally bioavailable ER PROTAC degrader GLR203801, with its binding affinity to cereblon increased by 20-fold than that of ARV-471. GLR203801 exhibited robust protein degradation in both ER wild-type cell lines (DC50 < 1 nM, Dmax> 90%) and mutant cell lines harboring Y537S or D538G mutation (DC50 2-10 nM, Dmax > 80%). Profound inhibition of the expression of ER-regulated genes GREB1 and PR was observed with GLR203801 in all the tested cell lines. GLR203801 shows more potent cell growth inhibition activity and maximum inhibition is 20%-30% higher than that of ARV-471 in all the tested ER wild-type and mutant cell lines. GLR203801 was characterized with favorable PK profile in vivo, with longer T1/2 and higher plasma exposure than ARV-471. GLR203801 displayed significantly enhanced antitumor efficacy than ARV-471 in five ER+ xenograft models (MCF-7, T-47D, ZR-75-1, MCF-7Y537S, and T-47DD538G), with tumor regression observed in wild-type xenograft models. PK/PD studies demonstrated that the tumor exposure of GLR203801 was 10 to 20-fold higher than that of ARV-471, and GLR203801 degraded >95% of ER in MCF-7WT and T-47DD538G tumor tissue. In addition, GLR203801 in combination with CDK4/6 inhibitors showed synergistic anti-tumor efficacy in T-47D xenograft model. GLR203801 also effectively inhibited the viability of breast-cancer patient derived ER+ organoids. The good tolerance of GLR203801 in toxicity study both in SD rats and beagle dogs supports it as a promising preclinical candidate for further clinical development. Citation Format: Guan Zhou, Yuanli Wang, Wei Xue, Yongzheng Ding, Jing Cheng, Kanghua Wang, Weiwei Yu, Wenmin Chen, Fuming Xu. Discovery of a highly potent and orally bioavailable ER PROTAC degrader for the treatment of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7021.