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

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. 2023 Dec:141:106919. doi: 10.1016/j.bioorg.2023.106919.
Chengfeng Bai 1,  Yang Lv 2,  Shuangshuang Xiong 1,  Shuangjie Wu 1,  Lin Qi 1,  Shengnan Ren 1,  Meiqi Zhu 1,  Haijuan Dong 3,  Hongtao Shen 2,  Zhaoxing Li 2,  Yinxue Zhu 4,  Hui Ye 4,  Haiping Hao 5,  Yibei Xiao 6,  Hua Xiang 7,  Guoshun Luo 8
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
  • 3 The Public Laboratory Platform, China Pharmaceutical University, Nanjing 210009, China.
  • 4 Jiangsu Provincial Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
  • 5 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.
  • 6 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.
  • 7 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.
  • 8 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.
PMID: 37871388 DOI: 10.1016/j.bioorg.2023.106919
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 ERαY537S (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.

Keywords

Breast cancer; Covalent antagonist; Estrogen receptor α; SERCAs.

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