2. Academic Validation
  3. Drug discovery of N-methyl-pyrazole derivatives as potent selective estrogen receptor degrader (SERD) for the treatment of breast cancer

Drug discovery of N-methyl-pyrazole derivatives as potent selective estrogen receptor degrader (SERD) for the treatment of breast cancer

  • Eur J Med Chem. 2024 Sep 23:279:116894. doi: 10.1016/j.ejmech.2024.116894.
Rupeng Dai 1,  Xueting Bao 1,  Chao Liu 2,  Xunkai Yin 1,  Zhenzhen Zhu 1,  Zhe Zheng 1,  Bo Wang 1,  Kundi Yang 3,  Hongmei Wen 4,  Wei Li 5,  Haohao Zhu 6,  Qianming Du 7,  Jian Liu 8
Affiliations

Affiliations

  • 1 School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
  • 2 Department of Pharmacy, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210029, China; School of Basic Medicine & Clinical Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
  • 3 Department of Chemistry and Biochemistry, Miami University, Oxford, OH, 45056, USA.
  • 4 School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China. Electronic address: njwenhm@126.com.
  • 5 School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China. Electronic address: liwaii@njucm.edu.cn.
  • 6 The Affiliated Mental Health Center of Jiangnan University, Wuxi Central Rehabilitation Hospital, Wuxi, Jiangsu, 214151, China. Electronic address: zhuhh@jiangnan.edu.cn.
  • 7 General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, China; Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: duqianming@njmu.edu.cn.
  • 8 School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China. Electronic address: liujian623@njucm.edu.cn.
PMID: 39357315 DOI: 10.1016/j.ejmech.2024.116894
Abstract

Nowadays, ERα is considered to be a primary target for the treatment of breast Cancer, and selective Estrogen Receptor degraders (SERDs) are emerging as promising antitumor agents. By analysing ERα-SERDs complexes, the pharmacophore features of SERDs and the crucial protein-ligand interactions were identified. Then, by utilizing the scaffold-hopping and bioisosteres strategy, 23 novel derivatives were designed, synthesized and biologically evaluated. Among these derivatives, A20 exhibited potent ERα binding affinity (IC50 = 24.0 nM), degradation ability (EC50 = 5.3 nM), excellent ER selectivity, and outstanding anti-proliferative effects on MCF-7 cells (IC50 = 0.28 nM). Further biological studies revealed that A20 could degrade ERα through proteasome-mediated pathway, suppress signal transduction of MCF-7 cells, and arrest the cell cycle in G1 phase. Moreover, A20 showed excellent antitumor effect (TGI = 92.98 %, 30 mg kg-1 day-1) in the MCF-7 xenograft model in vivo with good safety and favorable pharmacokinetics (F = 39.6 %), making it a promising candidate for the treatment of breast Cancer.

Keywords

Bioisosteres; Breast cancer; Estrogen receptor; Scaffold-hopping; Selective estrogen receptor degraders.

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