Targeted inhibition of the COP9 signalosome for treatment of cancer.
Nat Commun
; 7: 13166, 2016 10 24.
Article
en En
| MEDLINE
| ID: mdl-27774986
The COP9 signalosome (CSN) is a central component of the activation and remodelling cycle of cullin-RING E3 ubiquitin ligases (CRLs), the largest enzyme family of the ubiquitin-proteasome system in humans. CRLs are implicated in the regulation of numerous cellular processes, including cell cycle progression and apoptosis, and aberrant CRL activity is frequently associated with cancer. Remodelling of CRLs is initiated by CSN-catalysed cleavage of the ubiquitin-like activator NEDD8 from CRLs. Here we describe CSN5i-3, a potent, selective and orally available inhibitor of CSN5, the proteolytic subunit of CSN. The compound traps CRLs in the neddylated state, which leads to inactivation of a subset of CRLs by inducing degradation of their substrate recognition module. CSN5i-3 differentially affects the viability of tumour cell lines and suppresses growth of a human xenograft in mice. Our results provide insights into how CSN regulates CRLs and suggest that CSN5 inhibition has potential for anti-tumour therapy.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Pirazoles
/
Azepinas
/
Regulación Neoplásica de la Expresión Génica
/
Linfoma Anaplásico de Células Grandes
/
Ubiquitina-Proteína Ligasas
/
Péptidos y Proteínas de Señalización Intracelular
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Complejo del Señalosoma COP9
/
Antineoplásicos
Límite:
Animals
/
Female
/
Humans
Idioma:
En
Revista:
Nat Commun
Asunto de la revista:
BIOLOGIA
/
CIENCIA
Año:
2016
Tipo del documento:
Article
País de afiliación:
Suiza
Pais de publicación:
Reino Unido