E3-Specific Degrader Discovery by Dynamic Tracing of Substrate Receptor Abundance.
J Am Chem Soc
; 145(2): 1176-1184, 2023 01 18.
Article
em En
| MEDLINE
| ID: mdl-36602777
ABSTRACT
Targeted protein degradation (TPD) is a new pharmacology based on small-molecule degraders that induce proximity between a protein of interest (POI) and an E3 ubiquitin ligase. Of the approximately 600 E3s encoded in the human genome, only around 2% can be co-opted with degraders. This underrepresentation is caused by a paucity of discovery approaches to identify degraders for defined E3s. This hampers a rational expansion of the druggable proteome and stymies critical advancements in the field, such as tissue- and cell-specific degradation. Here, we focus on dynamic NEDD8 conjugation, a post-translational, regulatory circuit that controls the activity of 250 cullin RING E3 ligases (CRLs). Leveraging this regulatory layer enabled us to develop a scalable assay to identify compounds that alter the interactome of an E3 of interest by tracing their abundance after pharmacologically induced auto-degradation. Initial validation studies are performed for CRBN and VHL, but proteomics studies indicate broad applicability for many CRLs. Among amenable ligases, we select CRLDCAF15 for a proof-of-concept screen, leading to the identification of a novel DCAF15-dependent molecular glue degrader inducing the degradation of RBM23 and RBM39. Together, this strategy empowers the scalable identification of degraders specific to a ligase of interest.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteínas de Transporte
/
Ubiquitina-Proteína Ligases
Limite:
Humans
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article