2. Academic Validation
  3. Identification of Novel Dual-Target Estrogen Receptor α Degraders with Tubulin Inhibitory Activity for the Treatment of Endocrine-Resistant Breast Cancer

Identification of Novel Dual-Target Estrogen Receptor α Degraders with Tubulin Inhibitory Activity for the Treatment of Endocrine-Resistant Breast Cancer

  • J Med Chem. 2023 Aug 24;66(16):11094-11117. doi: 10.1021/acs.jmedchem.3c00465.
Xiangping Deng 1,  Xiaofei Deng 1,  Wentao Ning 1,  Lilan Xin 1,  Qiuzi Li 2,  Zhiye Hu 1,  Baohua Xie 1,  Kaiwei Liang 3,  Chang Min 1,  Chune Dong 1,  Jian Huang 2,  Hai-Bing Zhou 1 4
Affiliations

Affiliations

  • 1 Department of Hematology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China.
  • 2 College of Life Sciences, Wuhan University, Bayi Road, Wuhan 430072, China.
  • 3 Department of Pathophysiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China.
  • 4 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.
PMID: 37584263 DOI: 10.1021/acs.jmedchem.3c00465
Abstract

Endocrine resistance remains a significant problem in the clinical treatment of Estrogen Receptor α-positive (ERα+) breast Cancer (BC). In this study, we developed a series of novel dual-functional ERα degraders based on a bridged bicyclic scaffold with selenocyano (SeCN) side chains. These compounds displayed potent ERα degradation and tubulin depolymerization activity. Among them, compounds 35s and 35t exhibited the most promising antiproliferative and ERα degradation activity in multiple ERα+ BC cell lines bearing either wild-type or mutant ERα. Meanwhile, compounds 35s and 35t disrupted the microtubule network by restraining tubulin polymerization, evidenced by 35t inducing cell cycle arrest in the G2/M phase. In MCF-7 and LCC2 xenograft models, compounds 35s and 35t remarkably suppressed tumor growth without noticeable poisonousness. Finally, this study provided guidance for developing new dual-target antitumor drug candidates for the ERα+ BC therapy, especially for the resistant variant.

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