Drug discovery of N-methyl-pyrazole derivatives as potent selective estrogen receptor degrader (SERD) for the treatment of breast cancer.
Eur J Med Chem
; 279: 116894, 2024 Sep 23.
Article
em En
| MEDLINE
| ID: mdl-39357315
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.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Idioma:
En
Revista:
Eur J Med Chem
Ano de publicação:
2024
Tipo de documento:
Article