Design, synthesis, and biological evaluation of novel 8-substituted quercetin derivatives targeting the ßcatenin/B-cell lymphoma 9 interaction.
Bioorg Med Chem Lett
; 98: 129591, 2024 Jan 15.
Article
em En
| MEDLINE
| ID: mdl-38097141
ABSTRACT
The ß-catenin/B-cell lymphoma 9 (BCL9) protein-protein interaction (PPI) is a potential target for aberrantly active Wnt/ß-catenin signaling which actively participates in initiating and progressing of many cancers. Herein, we discovered novel 8-substituted quercetin derivatives with potential inhibitory activities targeting ß-catenin/BCL9 PPI. Among all the derivatives, compound B4 displayed the most promising PPI inhibitory activity with an IC50 value of 2.25 µM in a competitive fluorescence polarization assay and a KD value of 1.44 µM for the ß-catenin protein. Furthermore, B4 selectively inhibited the growth of colorectal cancer (CRC) cells, suppressed the transactivation of Wnt signaling, and downregulated the expression of oncogenic Wnt target gene. Especially, B4 showed potent anti-CRC activity in vivo with the tumor growth inhibition (TGI) of 75.99 % and regulated the tumor immune microenvironment.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Quercetina
/
Neoplasias Colorretais
/
Linfoma de Células B
/
Neoplasias
Limite:
Humans
Idioma:
En
Revista:
Bioorg Med Chem Lett
Assunto da revista:
BIOQUIMICA
/
QUIMICA
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
China