A homogeneous time-resolved fluorescence screen to identify SIRT2 deacetylase and defatty-acylase inhibitors.
PLoS One
; 19(6): e0305000, 2024.
Article
em En
| MEDLINE
| ID: mdl-38913635
ABSTRACT
Human sirtuin-2 (SIRT2) has emerged as an attractive drug target for a variety of diseases. The enzyme is a deacylase that can remove chemically different acyl modifications from protein lysine residues. Here, we developed a high-throughput screen based on a homogeneous time-resolved fluorescence (HTRF) binding assay to identify inhibitors of SIRT2's demyristoylase activity, which is uncommon among many ligands that only affect its deacetylase activity. From a test screen of 9600 compounds, we identified a small molecule that inhibited SIRT2's deacetylase activity (IC50 = 7 µM) as well as its demyristoylase activity (IC50 = 37 µM). The inhibitor was composed of two small fragments that independently inhibited SIRT2 a halogenated phenol fragment inhibited its deacetylase activity, and a tricyclic thiazolobenzimidazole fragment inhibited its demyristoylase activity. The high-throughput screen also detected multiple deacetylase-specific SIRT2 inhibitors.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Sirtuína 2
/
Ensaios de Triagem em Larga Escala
Limite:
Humans
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article