Exploiting the Cullin E3 Ligase Adaptor Protein SKP1 for Targeted Protein Degradation.
ACS Chem Biol
; 19(2): 442-450, 2024 02 16.
Article
en En
| MEDLINE
| ID: mdl-38305738
ABSTRACT
Targeted protein degradation with proteolysis targeting chimeras (PROTACs) is a powerful therapeutic modality for eliminating disease-causing proteins through targeted ubiquitination and proteasome-mediated degradation. Most PROTACs have exploited substrate receptors of Cullin-RING E3 ubiquitin ligases such as cereblon and VHL. Whether core, shared, and essential components of the Cullin-RING E3 ubiquitin ligase complex can be used for PROTAC applications remains less explored. Here, we discovered a cysteine-reactive covalent recruiter EN884 against the SKP1 adapter protein of the SKP1-CUL1-F-box containing the SCF complex. We further showed that this recruiter can be used in PROTAC applications to degrade neo-substrate proteins such as BRD4 and the androgen receptor in a SKP1- and proteasome-dependent manner. Our studies demonstrate that core and essential adapter proteins within the Cullin-RING E3 ubiquitin ligase complex can be exploited for targeted protein degradation applications and that covalent chemoproteomic strategies can enable recruiter discovery against these targets.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Ubiquitina-Proteína Ligasas
/
Proteínas Cullin
Idioma:
En
Revista:
ACS Chem Biol
/
ACS chem. biol. (Online)
/
ACS chemical biology (Online)
Año:
2024
Tipo del documento:
Article
País de afiliación:
Estados Unidos