Design, synthesis and biological evaluation of indole-2-one derivatives as potent BRD4 inhibitors.
Eur J Med Chem
; 208: 112780, 2020 Dec 15.
Article
en En
| MEDLINE
| ID: mdl-32883643
Bromodomain protein 4 (BRD4) plays a crucial role in transcriptional regulation and is considered to be a viable drug target for cancer treatment. Herein, we designed and synthesized a series of indole-2-one derivatives through scaffold hopping drug design. Most of the compounds showed potent BRD4 inhibitory activities and anti-proliferation activities in cancer cell lines. Especially, compound 12j exhibited excellent BRD4 inhibitory activities (BD1 IC50 = 19 nM, BD2 IC50 = 28 nM) and anti-proliferation potency with IC50 values of 4.75 µM and 1.35 µM in HT-29 and HL-60 cells, respectively. Additionally, docking studies showed that the hydrophobic pocket next to KAc region and WPF shelf were critical to the activity of the compound. Compound 12j could arrest the cell-cycle progression of HT-29 cells into the G1 phase and reduce the expression of c-Myc. Moreover, compound 12j exhibited favorable oral pharmacokinetic properties. All the results demonstrated that compound 12j was a potent BRD4 inhibitor and had merely potential for colon cancer treatment.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Factores de Transcripción
/
Proteínas de Ciclo Celular
/
Indoles
/
Antineoplásicos
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Eur J Med Chem
Año:
2020
Tipo del documento:
Article
País de afiliación:
China
Pais de publicación:
Francia