Structural evolution progress of orally bioavailable selective estrogen receptor degraders

Jiahe Zhang; Jiachen Zhang; Yingtong Zhao; Yibo Liu; Yan Sun; Hongrui Lei; Xin Zhai

doi:10.1016/j.bmc.2025.118288

Structural evolution progress of orally bioavailable selective estrogen receptor degraders

Bioorg Med Chem. 2025 Jun 19:128:118288. doi: 10.1016/j.bmc.2025.118288. Online ahead of print.

Authors

Jiahe Zhang¹, Jiachen Zhang¹, Yingtong Zhao¹, Yibo Liu¹, Yan Sun¹, Hongrui Lei², Xin Zhai³

Affiliations

¹ Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
² Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China. Electronic address: leighongray1023@163.com.
³ Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China. Electronic address: zhaixin_syphu@126.com.

PMID: 40555029
DOI: 10.1016/j.bmc.2025.118288

Abstract

The alpha subtype of the estrogen receptor (ERα) plays a crucial role in breast cancer as a target for endocrine therapy. Fulvestrant, developed by AstraZeneca as the first selective estrogen receptor degraders (SERDs), effectively downregulates ER levels by reducing its stability, which leads to degradation through protein degradation mechanisms. However, the administration of Fulvestrant via the intramuscular route has imposed significant limitations on its clinical application, prompting the exploration of active oral bioavailable SERDs. Furthermore, research institutes and pharmaceutical companies have evaluated the efficacy of various oral SERDs in terms of their ability to degrade the ER, binding capacity, safety profiles, and numerous other indicators. This paper reviews recent advancements in oral SERDs, discusses their evolutionary relationships, and outlines the processes of structural modification, providing valuable insights for future research and applications.

Keywords: Breast cancer; Estrogen receptor; Fulvestrant; Research progress; SERDs.

Publication types

Review