ChemRxiv
These are preliminary reports that have not been peer-reviewed. They should not be regarded as conclusive, guide clinical practice/health-related behavior, or be reported in news media as established information. For more information, please see our FAQs.
for ChemRxiv revised.pdf (3.44 MB)
0/0

Cereblon versus VHL: Hijacking E3 Ligases Against Each Other Using PROTACs

preprint
revised on 19.02.2019 and posted on 19.02.2019 by Miriam Girardini, Chiara Maniaci, Scott J. Hughes, Andrea Testa, Alessio Ciulli

The von Hippel-Lindau (VHL) and cereblon (CRBN) proteins are substrate recognition subunits of two ubiquitously expressed and biologically important Cullin RING E3 ubiquitin ligase complexes. VHL and CRBN are also the two most popular E3 ligases being recruited by bifunctional Proteolysis-targeting chimeras (PROTACs) to induce ubiquitination and subsequent proteasomal degradation of a target protein. Using homo-PROTACs, VHL and CRBN have been independently dimerized to induce their own degradation. Here we report the design, synthesis and cellular activity of VHL-CRBN hetero-dimerizing PROTACs featuring diverse conjugation patterns. We found that the most active compound 14a induced potent, rapid and profound preferential degradation of CRBN over VHL in cancer cell lines. At lower concentrations, weaker degradation of VHL was instead observed. This work demonstrates proof of concept of designing PROTACs to hijack different E3 ligases against each other, and highlights a powerful and generalizable proximity-induced strategy to achieve E3 ligase knockdown.

Funding

European Research Council (ERC) Starting Grant ERC-2012-StG-311460

State-of-the-art facilities for structural biology at the University of Dundee.

Wellcome Trust

Find out more...

History

Email Address of Submitting Author

a.ciulli@dundee.ac.uk

Institution

University of Dundee

Country

United Kingdom

ORCID For Submitting Author

0000-0002-8654-1670

Declaration of Conflict of Interest

The Ciulli laboratory receives sponsored research support from Boehringer Ingelheim and Nurix, Inc. A.C. is a scientific founder, director and shareholder of Amphista Therapeutics, a company that is developing targeted protein degradation therapeutic platforms.

Version Notes

First version of the manuscript. While this manuscript was in advanced stage of preparation, related hetero-bifunctional VHL-CRBN PROTACs were published by C. Steinebach et al. Chem. Commun., DOI: 10.1039/C8CC09541H as an Accepted Manuscript, in which preferential degradation of CRBN over VHL was also observed with a compound different from 14a.

Licence

Exports