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bioRxiv · 10.1101/2023.10.20.563371

Exploiting the Cullin E3 Ligase Adaptor Protein SKP1 for Targeted Protein Degradation

Hong, S. H.·Osa, A.·Wertz, I. E.·Nomura, D.
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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 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.

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Hong, S. H., Osa, A., Wertz, I. E., Nomura, D.. 2023-10-21. Exploiting the Cullin E3 Ligase Adaptor Protein SKP1 for Targeted Protein Degradation. https://doi.org/10.1101/2023.10.20.563371

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