E3-Specific Degrader Discovery by Dynamic Tracing of Substrate Receptor Abundance
2023
academicJournal
Zugriff:
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 CRL DCAF15 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.
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E3-Specific Degrader Discovery by Dynamic Tracing of Substrate Receptor Abundance
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Autor/in / Beteiligte Person: | Alexander Hanzl (14333466) ; Eleonora Barone (14333469) ; Sophie Bauer (4803567) ; Hong Yue (1608610) ; Radosław P. Nowak (11886680) ; Elisa Hahn (14333472) ; Eugenia V. Pankevich (14333475) ; Anna Koren (13282034) ; Stefan Kubicek (172383) ; Eric S. Fischer (5136572) ; Georg E. Winter (1565821) |
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Veröffentlichung: | 2023 |
Medientyp: | academicJournal |
DOI: | 10.1021/jacs.2c10784.s001 |
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