Targeted Covalent Inhibition of Small CTD Phosphatase 1 to Promote the Degradation of the REST Transcription Factor in Human Cells.
J Med Chem
; 65(1): 507-519, 2022 01 13.
Article
en En
| MEDLINE
| ID: mdl-34931516
ABSTRACT
The repressor element-1 silencing transcription factor (REST) represses neuronal gene expression, whose dysregulation is implicated in brain tumors and neurological diseases. A high level of REST protein drives the tumor growth in some glioblastoma cells. While transcription factors like REST are challenging targets for small-molecule inhibitors, the inactivation of a regulatory protein, small CTD phosphatase 1 (SCP1), promotes REST degradation and reduces transcriptional activity. This study rationally designed a series of α,ß-unsaturated sulfones to serve as potent and selective covalent inhibitors against SCP1. The compounds inactivate SCP1 via covalent modification of Cys181 located at the active site entrance. Cellular studies showed that the inhibitors inactivate SCP1 in a time- and dose-dependent manner with an EC50 â¼1.5 µM, reducing REST protein levels and activating specific REST-suppressed genes. These compounds represent a promising line of small-molecule inhibitors as a novel lead for glioblastoma whose growth is driven by REST transcription activity.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Proteínas Represoras
/
Fosfoproteínas Fosfatasas
/
Inhibidores Enzimáticos
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Año:
2022
Tipo del documento:
Article