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
  • 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: [email protected].
  • 5. School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China. Electronic address: [email protected].
  • 6. The Affiliated Mental Health Center of Jiangnan University, Wuxi Central Rehabilitation Hospital, Wuxi, Jiangsu, 214151, China. Electronic address: [email protected].
  • 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: [email protected].
  • 8. School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China. Electronic address: [email protected].
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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