Discovery and optimization of dihydropteridone derivatives as novel PLK1 and BRD4 dual inhibitor for the treatment of cancer.
Bioorg Med Chem
; 101: 117609, 2024 Mar 01.
Article
em En
| MEDLINE
| ID: mdl-38364599
ABSTRACT
In this study, we have designed, synthesized and tested three series of novel dihydropteridone derivatives possessing isoindolin-1-one or isoindoline moieties as potent inhibitors of PLK1/BRD4. Remarkably, most of the compounds showed preferable inhibitory activity against PLK1 and BRD4. Compound SC10 exhibited excellent inhibitory activity with IC50 values of 0.3â¯nM and 60.8â¯nM against PLK1 and BRD4, respectively. Meanwhile, it demonstrated significant anti-proliferative activities against three tumor-derived cell lines (MDA-MB-231 IC50â¯=â¯17.3â¯nM, MDA-MB-361 IC50â¯=â¯8.4â¯nM, and MV4-11 IC50â¯=â¯5.4â¯nM). Moreover, SC10 exhibited moderate rat liver microsomal stability (CLintâ¯=â¯21.3⯵L·min-1·mg-1), acceptable pharmacokinetic profile (AUC0-tâ¯=â¯657â¯ng·h·mL-1, oral bioavailability of 21.4â¯%) in Sprague-Dawley rats, reduced hERG toxicity, acceptable PPB and CYP450 inhibition. Further research indicated that SC10 could induce MV4-11 cell arrest at the S phase and apoptosis in a dose-dependent manner. This investigation provided us with an initial point for developing novel anticancer agents as dual inhibitors of PLK1 and BRD4.
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Texto completo:
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Inibidores de Proteínas Quinases
/
Neoplasias
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Antineoplásicos
Limite:
Animals
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article