7WNV

Crystal structure of mutant estrogen receptor alpha Y537S in complex with CO9

Summary for 7WNV

• Entry DOI: 10.2210/pdb7wnv/pdb
• Descriptor: Estrogen receptor, (~{Z})-4-[2-[4-[[2-(4-hydroxyphenyl)-6-oxidanyl-1-benzothiophen-3-yl]oxy]phenoxy]ethylamino]-~{N},~{N}-dimethyl-but-2-enamide (3 entities in total)
• Functional Keywords: covalent inhibitor transcription factor oncogene, nuclear protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 120025.34

Authors

Xiao, Y.,Lv, Y. (deposition date: 2022-01-19, release date: 2023-01-25, Last modification date: 2024-10-16)

Primary citation

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.
X-ray crystallography study and optimization of novel benzothiophene analogs as potent selective estrogen receptor covalent antagonists (SERCAs) with improved potency and safety profiles.
Bioorg.Chem., 141:106919-106919, 2023

PubMed Abstract: Endocrine therapy (ET) is a well-validated strategy for estrogen receptor α positive (ERα + ) 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 ERα negative (ERα-) cells. More importantly, their mode of covalent engagement at Cys530 residue was accurately illustrated by a cocrystal structure of 15b-bound ERα (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 ERα + breast cancer.

PubMed: 37871388
DOI: 10.1016/j.bioorg.2023.106919

Experimental method

X-RAY DIFFRACTION (2.3 Å)