2. Academic Validation
  3. Highly potent and selective degrader targeting ERα to improve the treatment outcomes of breast cancer

Highly potent and selective degrader targeting ERα to improve the treatment outcomes of breast cancer

  • Eur J Med Chem. 2026 Jan 5:301:118199. doi: 10.1016/j.ejmech.2025.118199.
Xueting Bao 1,  Xunkai Yin 1,  Jinjing Xu 2,  ZhenZhen Zhu 1,  Wenyu Lu 3,  Yihui Cai 3,  Rupeng Dai 1,  Zhe Zheng 1,  Wenzhuo Xu 1,  Shulan Mei 1,  Songyun Xu 1,  Jie Li 4,  Nianguang Li 5,  Haohao Zhu 6,  Jianing Wang 7,  Jian Liu 8
Affiliations

Affiliations

  • 1 School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, PR China.
  • 2 Otorhinolaryngology Head and Neck Surgery, Nanjing Pukou People's Hospital, Liangjiang Hospital, Southeast University, Nanjing, 211198, PR China.
  • 3 School of Artificial Intelligence and Information Technology, Nanjing University of Chinese Medicine, Nanjing, 210023, PR China.
  • 4 Department of Pharmacy, Zhangjiagang TCM Hospital, Affiliated to Nanjing University of Chinese Medicine, Suzhou, Jiangsu, 215600, PR China. Electronic address: [email protected].
  • 5 School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, PR China. Electronic address: [email protected].
  • 6 The Affiliated Mental Health Center of Jiangnan University, Wuxi Central Rehabilitation Hospital, Wuxi, 214151, PR China. Electronic address: [email protected].
  • 7 Department of Pharmacy, The Affiliated Jiangning Hospital with Nanjing Medical University, Nanjing, 211100, PR China. Electronic address: [email protected].
  • 8 School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, PR China. Electronic address: [email protected].
PMID: 41037982 DOI: 10.1016/j.ejmech.2025.118199
Abstract

Estrogen receptor alpha (ERα) is overexpressed in approximately 70 % of breast Cancer cases; therefore, it is considered a primary therapeutic target for breast Cancer. Several therapeutic agents, including selective Estrogen receptor modulators, aromatase inhibitors, selective Estrogen receptor degraders, and proteolysis-targeting chimeras (PROTACs), have been developed to antagonize and degrade ERα. The representative ERα-targeting PROTAC (ERα-PROTAC) agent ARV-471 has been used to treat locally advanced or metastatic breast Cancer in clinical trials. Herein, we designed, synthesized, and evaluated several novel ERα-PROTAC agents. After systematic structural optimization, compound A16 was found to have excellent antiproliferative and ERα-inhibitory activities in the breast Cancer cell line MCF-7. A16 selectively degraded ERα (DC50 = 3.78 nM) through the ubiquitin-proteasome pathway in a time- and concentration-dependent manner. It effectively attenuated drug resistance (MCF-7 Y537S cells; IC50 = 1.3 nM), inhibited proliferation, and induced Apoptosis in MCF-7 cells. In addition, it exhibited excellent antitumor effects (10 mg/kg/d intraperitoneal injection; total growth inhibition = 80.11 %) and a good safety profile in an MCF-7 xenograft model, highlighting its potential as a novel drug candidate for breast Cancer.

Keywords

Breast cancer; Drug resistance; E3 ligase ligand; Estrogen receptor; PROTAC.

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