2. Academic Validation
  3. Exploiting the Cullin E3 Ligase Adaptor Protein SKP1 for Targeted Protein Degradation

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

  • bioRxiv. 2023 Nov 2:2023.10.20.563371. doi: 10.1101/2023.10.20.563371.
Seong Ho Hong 1 2,  Akane Osa 1 2,  Oscar W Huang 3,  Ingrid E Wertz 3,  Daniel K Nomura 1 2 4
Affiliations

Affiliations

  • 1 Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720 USA.
  • 2 Innovative Genomics Institute, Berkeley, CA 94720 USA.
  • 3 Bristol Myers Squibb, Brisbane, CA 94158 USA.
  • 4 Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720 USA.
PMID: 37904950 DOI: 10.1101/2023.10.20.563371
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.

Keywords

AR; BRD4; CUL1; SKP1; activity-based protein profiling; androgen receptor; chemoproteomics; covalent; targeted protein degradation.

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