7wnv

Publication Abstract from PubMed

Endocrine therapy (ET) is a well-validated strategy for estrogen receptor alpha positive (ERalpha + ) breast cancer therapy. Despite the clinical success of current standard of care (SoC), endocrine-resistance inevitably emerges and remains a significant medical challenge. Herein, we describe the structural optimization and evaluation of a new series of selective estrogen receptor covalent antagonists (SERCAs) based on benzothiophene scaffold. Among them, compounds 15b and 39d were identified as two highly potent covalent antagonists, which exhibits superior antiproliferation activity than positive controls against MCF-7 cells and shows high selectivity over ERalpha negative (ERalpha-) cells. More importantly, their mode of covalent engagement at Cys530 residue was accurately illustrated by a cocrystal structure of 15b-bound ERalpha(Y537S) (PDB ID: 7WNV) and intact mass spectrometry, respectively. Further in vivo studies demonstrated potent antitumor activity in MCF-7 xenograft mouse model and an improved safety profile. Collectively, these compounds could be promising candidates for future development of the next generation SERCAs for endocrine-resistant ERalpha + breast cancer.

X-ray crystallography study and optimization of novel benzothiophene analogs as potent selective estrogen receptor covalent antagonists (SERCAs) with improved potency and safety profiles.,Bai C, Lv Y, Xiong S, Wu S, Qi L, Ren S, Zhu M, Dong H, Shen H, Li Z, Zhu Y, Ye H, Hao H, Xiao Y, Xiang H, Luo G Bioorg Chem. 2023 Dec;141:106919. doi: 10.1016/j.bioorg.2023.106919. Epub 2023 , Oct 14. PMID:37871388^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.