X-ray crystallography study and optimization of novel benzothiophene analogs as potent selective estrogen receptor covalent antagonists (SERCAs) with improved potency and safety profiles.

Humans Mice Animals Female Estrogen Receptor Antagonists Estrogen Receptor alpha Receptors, Estrogen Crystallography, X-Ray Breast Neoplasms / drug therapy MCF-7 Cells Estrogen Antagonists
Breast cancer Covalent antagonist Estrogen receptor α SERCAs

Journal

Bioorganic chemistry
ISSN: 1090-2120
Titre abrégé: Bioorg Chem
Pays: United States
ID NLM: 1303703

Informations de publication

Date de publication:
12 2023
Historique:
received: 29 08 2023
revised: 12 10 2023
accepted: 13 10 2023
medline: 3 11 2023
pubmed: 24 10 2023
entrez: 23 10 2023
Statut: ppublish

Résumé

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

Identifiants

DOI: 10.1016/j.bioorg.2023.106919 PMID: 37871388
pubmed: 37871388
pii: S0045-2068(23)00580-1
doi: 10.1016/j.bioorg.2023.106919
pii:
doi:

Substances chimiques

Estrogen Receptor Antagonists 0
Estrogen Receptor alpha 0
Receptors, Estrogen 0
benzothiophene 073790YQ2G
Estrogen Antagonists 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

106919

Informations de copyright

Copyright © 2023 Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Auteurs

Chengfeng Bai (C)

Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.

Yang Lv (Y)

Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.

Shuangshuang Xiong (S)

Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.

Shuangjie Wu (S)

Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.

Lin Qi (L)

Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.

Shengnan Ren (S)

Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.

Meiqi Zhu (M)

Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.

Haijuan Dong (H)

The Public Laboratory Platform, China Pharmaceutical University, Nanjing 210009, China.

Hongtao Shen (H)

Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.

Zhaoxing Li (Z)

Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.

Yinxue Zhu (Y)

Jiangsu Provincial Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.

Hui Ye (H)

Jiangsu Provincial Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.

Haiping Hao (H)

Jiangsu Provincial Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.

Yibei Xiao (Y)

Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China. Electronic address: yibei.xiao@cpu.edu.cn.

Hua Xiang (H)

Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China. Electronic address: xianghua@cpu.edu.cn.

Guoshun Luo (G)

Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China. Electronic address: gsluo@cpu.edu.cn.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › X-ray crystallography study and optimization...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › X-ray crystallography study and optimization...
questionsmedicales.fr › Eucaryotes › Animaux › X-ray crystallography study and optimization...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Effets physiologiques des médicaments › Hormones, substituts d'hormones et antagonistes d'hormones › Antihormones › Antagonistes des oestrogènes › Antagonistes des récepteurs des oestrogènes › X-ray crystallography study and optimization...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Récepteurs cytoplasmiques et nucléaires › Récepteur alpha des oestrogènes › X-ray crystallography study and optimization...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Récepteurs aux stéroïdes › Récepteurs des oestrogènes › X-ray crystallography study and optimization...
questionsmedicales.fr › Techniques d'investigation › Techniques de chimie analytique › Cristallographie aux rayons X › X-ray crystallography study and optimization...
questionsmedicales.fr › Maladies de la peau et du tissu conjonctif › Maladies de la peau › Maladies du sein › Tumeurs du sein › X-ray crystallography study and optimization...
questionsmedicales.fr › Cellules › Cellules cultivées › Lignée cellulaire › Cellules MCF-7 › X-ray crystallography study and optimization...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Effets physiologiques des médicaments › Hormones, substituts d'hormones et antagonistes d'hormones › Antihormones › Antagonistes des oestrogènes › X-ray crystallography study and optimization...