2. Academic Validation
  3. Design, synthesis and biological evaluation of fluorinated selective estrogen receptor degraders (FSERDs) --- A promising strategy for advanced ER positive breast cancer

Design, synthesis and biological evaluation of fluorinated selective estrogen receptor degraders (FSERDs) --- A promising strategy for advanced ER positive breast cancer

  • Eur J Med Chem. 2023 May 5;253:115324. doi: 10.1016/j.ejmech.2023.115324.
Yunlong Lu 1,  Chao Liu 2,  Xin Wang 3,  Lijuan Liu 3,  Zhihao Zhao 3,  Zhenlin Liang 3,  Yuanhao Liu 3,  Zhenfan Wen 3,  Qianming Du 4,  Wukun Liu 5
Affiliations

Affiliations

  • 1 Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, PR China; State Key Laboratory of Coordination Chemistry, Nanjing University, Nanjing, 210023, PR China.
  • 2 Department of Pharmacy, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210029, PR China; School of Basic Medicine & Clinical Pharmacy, China Pharmaceutical University, Nanjing, 210009, PR China.
  • 3 Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, PR China.
  • 4 General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, PR China; School of Basic Medicine & Clinical Pharmacy, China Pharmaceutical University, Nanjing, 210009, PR China. Electronic address: [email protected].
  • 5 Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, PR China; State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Guangxi Normal University, 541004, Guilin, PR China; State Key Laboratory of Coordination Chemistry, Nanjing University, Nanjing, 210023, PR China. Electronic address: [email protected].
PMID: 37019030 DOI: 10.1016/j.ejmech.2023.115324
Abstract

Although endocrine therapies involving pharmaceuticals, such as tamoxifen and Aromatase inhibitors, had initially demonstrated good responses in patients with estrogen receptor-positive (ER+) breast Cancer, they often led to drug resistance. ER plays a vital role in the progression of metastatic diseases. Fulvestrant, a first generation selective Estrogen Receptor degrader (SERD), can effectively downregulate the ER protein and inhibit its downstream signaling pathways. However, as the drug needs to be intramuscularly injected, its widespread use is limited owing to poor patient compliance. Herein, we described a novel class of orally bioavailable fluorine-substituted SERDs that exhibit improved pharmacokinetic profiles. We substituted the hydroxyl group of clinical SERD candidate 6 with a fluorine atom to diminish phase II metabolism. The subsequent structure-activity relationship (SAR) investigation identified 22h and 27b, which can effectively degrade ER in a dose-dependent manner and exhibit considerable antiproliferative potency and efficacy in vitro and in vivo. The excellent pharmacokinetic profiles of 27b render it promising candidate of clinically useful oral SERD.

Keywords

Breast cancer; ER; Endocrine therapy; Fulvestrant; SERDs.

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