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  3. Structure-guided identification of novel dual-targeting estrogen receptor α degraders with aromatase inhibitory activity for the treatment of endocrine-resistant breast cancer

Structure-guided identification of novel dual-targeting estrogen receptor α degraders with aromatase inhibitory activity for the treatment of endocrine-resistant breast cancer

  • Eur J Med Chem. 2023 May 5;253:115328. doi: 10.1016/j.ejmech.2023.115328.
Lilan Xin 1,  Jian Min 2,  Hebing Hu 2,  Yuanyuan Li 1,  Chuanqian Du 1,  Baohua Xie 1,  Yan Cheng 1,  Xiaofei Deng 1,  Xiangping Deng 1,  Kang Shen 1,  Jian Huang 3,  Chun-Chi Chen 2,  Rey-Ting Guo 4,  Chune Dong 5,  Hai-Bing Zhou 6
Affiliations

Affiliations

  • 1 Department of Gynecological Oncology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China.
  • 2 State Key Laboratory of Biocatalysis and Enzyme Engineering, Hubei Hongshan Laboratory, Hubei Collaborative Innovation Center for Green Transformation of Bio-Resources, Hubei Key Laboratory of Industrial Biotechnology, School of Life Sciences, Hubei University, Wuhan, 430062, China.
  • 3 Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, 430072, China.
  • 4 State Key Laboratory of Biocatalysis and Enzyme Engineering, Hubei Hongshan Laboratory, Hubei Collaborative Innovation Center for Green Transformation of Bio-Resources, Hubei Key Laboratory of Industrial Biotechnology, School of Life Sciences, Hubei University, Wuhan, 430062, China. Electronic address: [email protected].
  • 5 Department of Gynecological Oncology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China. Electronic address: [email protected].
  • 6 Department of Gynecological Oncology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China; Frontier Science Center for Immunology and Metabolism, State Key Laboratory of Virology, Provincial Key Laboratory of Developmentally Originated Disease, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (MOE) and Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals, Wuhan University, Wuhan, 430071, China. Electronic address: [email protected].
PMID: 37037140 DOI: 10.1016/j.ejmech.2023.115328
Abstract

Drug resistance is a major challenge in conventional endocrine therapy for Estrogen Receptor (ER) positive breast Cancer (BC). BC is a multifactorial disease, in which simultaneous Aromatase (ARO) inhibition and ERα degradation may effectively inhibit the signal transduction of both proteins, thus potentially overcoming drug resistance caused by overexpression or mutation of target proteins. In this study, guided by the X-ray structure of a hit compound 30a in complex with ER-Y537S, a structure-based optimization was performed to get a series of multiacting inhibitors targeting both ERα and ARO, and finally a novel class of potent selective Estrogen Receptor degraders (SERDs) based on a three-dimensional oxabicycloheptene sulfonamide (OBHSA) scaffold equipped with Aromatase Inhibitor (AI) activity were identified. Of these dual-targeting SERD-AI hybrids, compound 31q incorporating a 1H-1,2,4-triazole moiety showed excellent ERα degradation activity, ARO inhibitory activity and remarkable antiproliferative activity against BC resistant cells. Furthermore, 31q manifested efficient tumor suppression in MCF-7 tumor xenograft models. Taken together, our study reported for the first time the highly efficient dual-targeting SERD-AI hybrid compounds, which may lay the foundation of translational research for improved treatment of endocrine-resistant BC.

Keywords

Aromatase inhibitors; Breast cancer; Dual-targeting; Estrogen receptor α; Selective estrogen receptor degraders.

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