Design and synthesis of N-(1-(6-(substituted phenyl)-pyridazin-3-yl)-piperidine-3-yl)-amine derivatives as JMJD6 inhibitors.
Bioorg Chem
; 129: 106119, 2022 Dec.
Article
em En
| MEDLINE
| ID: mdl-36116323
ABSTRACT
JMJD6 is a member of the JmjC domain-containing family and has been identified as a promising therapeutic target for treating estrogen-induced and triple-negative breast cancer. To develop novel anti-breast cancer agents, we synthesized a class of N-(1-(6-(substituted phenyl)-pyridazine-3-yl)-piperidine-3-yl)-amine derivatives as potential JMJD6 inhibitors. Among them, the anti-cancer compound A29 was an excellent JMJD6 binder (KD = 0.75 ± 0.08 µM). It could upregulate the mRNA and protein levels of p53 and its downstream effectors p21 and PUMA by inhibiting JMJD6. Besides, A29 displayed potent anti-proliferative activities against tested breast cancer cells by the induction of cell apoptosis and cell cycle arrest. Significantly, A29 also promoted a remarkable reduction in tumor growth, with a TGI value of 66.6% (50 mg/kg, i.p.). Taken together, our findings suggest that A29 is a potent JMJD6 inhibitor bearing a new scaffold acting as a promising drug candidate for the treatment of breast cancer.
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Base de dados:
MEDLINE
Assunto principal:
Neoplasias de Mama Triplo Negativas
/
Antineoplásicos
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article