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

• Published in: ACS chemical biology 2024-02, Vol.19 (2), p.442-450
• Main Authors: Hong, Seong Ho, Divakaran, Anand, Osa, Akane, Huang, Oscar W., Wertz, Ingrid E., Nomura, Daniel K.
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Cullin Proteins - metabolism; Nuclear Proteins - metabolism; Proteasome Endopeptidase Complex - metabolism; Proteolysis; S-Phase Kinase-Associated Proteins - metabolism; Transcription Factors - metabolism; Ubiquitin-Protein Ligases - metabolism
• ISSN: 1554-8929; 1554-8937; 1554-8937
• DOI: 10.1021/acschembio.3c00642

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.