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

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 p...

Full description

Saved in:
Bibliographic Details
Published in:European journal of medicinal chemistry 2023-05, Vol.253, p.115328, Article 115328
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: Article
Language:English
Subjects:
Aromatase - metabolism
Aromatase inhibitors
Aromatase Inhibitors - pharmacology
Aromatase Inhibitors - therapeutic use
Breast cancer
Breast Neoplasms - drug therapy
Breast Neoplasms - pathology
Dual-targeting
Estrogen Antagonists - pharmacology
Estrogen Receptor alpha - metabolism
Estrogen receptor α
Female
Humans
Receptors, Estrogen - metabolism
Selective estrogen receptor degraders
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0223-5234
1768-3254
1768-3254
DOI:10.1016/j.ejmech.2023.115328