Cereblon versus VHL: Hijacking E3 ligases against each other using PROTACs

Area of Science:

• Biochemistry
• Molecular Biology
• Medicinal Chemistry

Background:

• Von Hippel-Lindau (VHL) and cereblon (CRBN) are key substrate recognition subunits of Cullin RING E3 ubiquitin ligase complexes.
• These E3 ligases are crucial targets for Proteolysis-targeting chimeras (PROTACs) in targeted protein degradation.
• Previous studies utilized homo-PROTACs to induce self-degradation of VHL or CRBN.

Purpose of the Study:

• To design, synthesize, and evaluate VHL-CRBN hetero-dimerizing PROTACs.
• To investigate the efficacy of these PROTACs in inducing degradation of VHL and CRBN.
• To establish a proof-of-concept for hijacking distinct E3 ligases against each other using PROTACs.

Main Methods:

• Design and synthesis of novel VHL-CRBN hetero-dimerizing PROTACs with varied conjugation strategies.
• Assessment of cellular activity and protein degradation in cancer cell lines.
• Comparative analysis of CRBN and VHL degradation induced by the PROTACs.

Main Results:

• The developed hetero-dimerizing PROTACs successfully induced degradation of VHL and CRBN.
• Compound 14a exhibited potent, rapid, and preferential degradation of CRBN over VHL.
• Lower concentrations of compound 14a resulted in observable degradation of VHL.

Conclusions:

• This work demonstrates the feasibility of designing PROTACs to induce degradation of distinct E3 ligases.
• The findings highlight a powerful and generalizable proximity-induced strategy for targeted E3 ligase knockdown.
• This approach offers a novel therapeutic strategy for diseases involving E3 ligase dysregulation.