Discovery of Effective Dual PROTAC Degraders with Synergistic Antitumor Activity for Overcoming Tamoxifen-Resistant Breast Cancer

  • J Med Chem. 2026 Jul 23;69(14):17291-17309. doi: 10.1021/acs.jmedchem.6c01189.
Lilan Xin  1 ,  Jing Liu  2 ,  Xinyi Guo  1 ,  Shengnan Li  1 ,  Zhangxiao Guo  1 ,  Hongli Wang  1 ,  Zemin Song  3 ,  Xiaofei Deng  1 ,  Chao Wang  1 ,  Pingping Fang  3 ,  Jian Huang  2 ,  Chune Dong  1  4 ,  Hai-Bing Zhou  1  4  3
Affiliations
  • 1. Department of Hematology, Zhongnan Hospital of Wuhan University School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China.
  • 2. Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, School of Life Sciences, Wuhan University, Wuhan 430072, China.
  • 3. Taikang Center for Life and Medical Sciences, 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: 42411996 DOI: 10.1021/acs.jmedchem.6c01189
Abstract

Endocrine therapies for estrogen receptor-positive (ER+) breast Cancer (BC) often encounter primary or acquired resistance, and elevated expression of histone deacetylase 6 (HDAC6) exacerbates therapeutic challenges. Emerging evidence indicates that simultaneous attenuation of Estrogen receptor α (ERα) and HDAC6 activities represents a promising strategy to overcome endocrine resistance. Herein, we report a novel hybrid ERα/HDAC6 dual-targeting PROTAC V-12c, which selectively degraded ERα and HDAC6 in vitro and in vivo and exhibited superior antiproliferation efficacy across a panel of BC cell lines. Mechanistically, V-12c degraded both ERα and HDAC6 via the Proteasome pathway, induced cell cycle arrest and Apoptosis, attenuated hormonal response, disrupted the autophagy-lysosome function, and triggered Ferroptosis, collectively contributing to overcoming tamoxifen resistance. Importantly, V-12c potently suppressed tumor growth in endocrine-resistant BC models, outperforming single-target therapies. This study identified a multimechanistic action of dual PROTAC V-12c with potent antitumor effects, providing a promising therapeutic strategy for endocrine-resistant BC.

Products