Targeted Degradation of Transcription Coactivator SRC-1 through the N-Degron Pathway.
Angew Chem Int Ed Engl
; 59(40): 17548-17555, 2020 09 28.
Article
en En
| MEDLINE
| ID: mdl-33026161
Aberrantly elevated steroid receptor coactivator-1 (SRC-1) expression and activity are strongly correlated with cancer progression and metastasis. Here we report, for the first time, the development of a proteolysis targeting chimera (PROTAC) that is composed of a selective SRC-1 binder linked to a specific ligand for UBR box, a unique class of E3 ligases recognizing N-degrons. We showed that the bifunctional molecule efficiently and selectively induced the degradation of SRC-1 in cells through the N-degron pathway. Importantly, given the ubiquitous expression of the UBR protein in most cells, PROTACs targeting the UBR box could degrade a protein of interest regardless of cell types. We also showed that the SRC-1 degrader significantly suppressed cancer cell invasion and migration in vitro and in vivo. Together, these results demonstrate that the SRC-1 degrader can be an invaluable chemical tool in the studies of SRC-1 functions. Moreover, our findings suggest PROTACs based on the N-degron pathway as a widely useful strategy to degrade disease-relevant proteins.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Péptidos
/
Ubiquitina-Proteína Ligasas
/
Coactivador 1 de Receptor Nuclear
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Angew Chem Int Ed Engl
Año:
2020
Tipo del documento:
Article
País de afiliación:
Corea del Sur
Pais de publicación:
Alemania