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

Autor: Dai R; School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China., Bao X; School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China., Liu C; Department of Pharmacy, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210029, China; School of Basic Medicine & Clinical Pharmacy, China Pharmaceutical University, Nanjing, 210009, China., Yin X; School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China., Zhu Z; School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China., Zheng Z; School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China., Wang B; School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China., Yang K; Department of Chemistry and Biochemistry, Miami University, Oxford, OH, 45056, USA., Wen H; School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China. Electronic address: njwenhm@126.com., Li W; School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China. Electronic address: liwaii@njucm.edu.cn., Zhu H; The Affiliated Mental Health Center of Jiangnan University, Wuxi Central Rehabilitation Hospital, Wuxi, Jiangsu, 214151, China. Electronic address: zhuhh@jiangnan.edu.cn., Du Q; 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., Liu J; School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China. Electronic address: liujian623@njucm.edu.cn.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2024 Dec 05; Vol. 279, pp. 116894. Date of Electronic Publication: 2024 Sep 23.
DOI: 10.1016/j.ejmech.2024.116894
Abstrakt: 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 (IC 50  = 24.0 nM), degradation ability (EC 50  = 5.3 nM), excellent ER selectivity, and outstanding anti-proliferative effects on MCF-7 cells (IC 50  = 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.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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