Structure-guided identification of novel dual-targeting estrogen receptor α degraders with aromatase inhibitory activity for the treatment of endocrine-resistant breast cancer

• Published in: European journal of medicinal chemistry Vol. 253; pp. 115328 - 115346
• Main Authors: Xin, Lilan, Min, Jian, Hu, Hebing, Li, Yuanyuan, Du, Chuanqian, Xie, Baohua, Cheng, Yan, Deng, Xiaofei, Deng, Xiangping, Shen, Kang, Huang, Jian, Chen, Chun-Chi, Guo, Rey-Ting, Dong, Chune, Zhou, Hai-Bing
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 05.05.2023; Elsevier
• Subjects: Aromatase - metabolism; Aromatase inhibitors; Aromatase Inhibitors - pharmacology; Aromatase Inhibitors - therapeutic use; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - pathology; Chemistry, Medicinal; Dual-targeting; Estrogen Antagonists - pharmacology; Estrogen Receptor alpha - metabolism; Estrogen receptor α; Female; Humans; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Receptors, Estrogen - metabolism; Science & Technology; Selective estrogen receptor degraders; Estrogen receptor α; Selective estrogen receptor degraders; Dual-targeting; Breast cancer; Aromatase inhibitors; DESIGN; DOWNREGULATORS SERDS; STATISTICS; MODULATORS; MECHANISMS; DISCOVERY; ER-ALPHA; Estrogen receptor alpha; OPTIMIZATION; ANTAGONISTS; DERIVATIVES
• ISSN: 0223-5234; 1768-3254; 1768-3254
• DOI: 10.1016/j.ejmech.2023.115328

Drug resistance is a major challenge in conventional endocrine therapy for estrogen receptor (ER) positive breast cancer (BC). BC is a multifactorial disease, in which simultaneous aromatase (ARO) inhibition and ERα degradation may effectively inhibit the signal transduction of both proteins, thus potentially overcoming drug resistance caused by overexpression or mutation of target proteins. In this study, guided by the X-ray structure of a hit compound 30a in complex with ER-Y537S, a structure-based optimization was performed to get a series of multiacting inhibitors targeting both ERα and ARO, and finally a novel class of potent selective estrogen receptor degraders (SERDs) based on a three-dimensional oxabicycloheptene sulfonamide (OBHSA) scaffold equipped with aromatase inhibitor (AI) activity were identified. Of these dual-targeting SERD-AI hybrids, compound 31q incorporating a 1H-1,2,4-triazole moiety showed excellent ERα degradation activity, ARO inhibitory activity and remarkable antiproliferative activity against BC resistant cells. Furthermore, 31q manifested efficient tumor suppression in MCF-7 tumor xenograft models. Taken together, our study reported for the first time the highly efficient dual-targeting SERD-AI hybrid compounds, which may lay the foundation of translational research for improved treatment of endocrine-resistant BC. [Display omitted] •Novel dual-target ER degraders with aromatase inhibitory activity were identified.•31q showed excellent ERα degradation activity and aromatase inhibitory activity.•31q showed remarkable antiproliferative activity against BC resistant cells.•31q manifested efficient tumor suppression in MCF-7 tumor xenograft models.