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

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Discovery

Background:

• Targeted protein degradation using Proteolysis Targeting Chimeras (PROTACs) offers a therapeutic strategy for disease-causing protein elimination via ubiquitination and proteasomal degradation.
• Current PROTACs primarily utilize substrate receptors from Cullin-RING E3 ubiquitin ligases like cereblon and VHL.
• The potential of core components within the Cullin-RING E3 ubiquitin ligase complex for PROTAC applications remains underexplored.

Approach:

• Discovered a novel cysteine-reactive covalent recruiter, EN884, targeting the SKP1 adapter protein within the SCF (SKP1-CUL1-F-box) complex.
• Utilized EN884 in PROTAC design to achieve targeted degradation of neo-substrates, including BRD4 and the androgen receptor.
• Demonstrated SKP1 and proteasome dependency for the observed degradation effects.

Key Points:

• Exploited the SKP1 adapter protein, a core component of the SCF E3 ubiquitin ligase complex, for PROTAC-mediated protein degradation.
• Successfully degraded neo-substrate proteins BRD4 and androgen receptor using SKP1-targeting PROTACs.
• Established the feasibility of using covalent chemoproteomic methods for discovering recruiters against essential E3 ligase complex components.

Conclusions:

• Core adapter proteins within Cullin-RING E3 ubiquitin ligase complexes are viable targets for novel PROTAC applications.
• Covalent chemoproteomic strategies are effective for identifying recruiters against these essential protein degradation machinery components.
• This work expands the targeting scope of PROTAC technology for therapeutic protein elimination.