Homo-PROTACs: bivalent small-molecule dimerizers of the VHL E3 ubiquitin ligase to induce self-degradation

Chiara Maniaci, Scott J. Hughes, Andrea Testa, Wenzhang Chen, Douglas J. Lamont, Sonia Rocha, Dario R. Alessi, Roberto Romeo, Alessio Ciulli (Lead / Corresponding author)

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167 Citations (Scopus)
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E3 ubiquitin ligases are key enzymes within the ubiquitin proteasome system which catalyze the ubiquitination of proteins, targeting them for proteasomal degradation. E3 ligases are gaining im-portance as targets to small molecules, both for direct inhibition and to be hijacked to induce the degradation of non-native neo substrates using bivalent compounds known as PROTACs (for “proteolysis targeting chimeras”). We describe Homo-PROTACs as an approach to dimerize an E3 ligase to trigger its suicide-type chemical knockdown inside cells. We provide proof-of-concept of Homo-PROTACs using diverse molecules composed of two instances of a ligand for the von Hippel-Lindau (VHL) E3 ligase. The most active compound, CM11, dimerizes VHL with high avidity in vitro and induces potent, rapid and proteasome-dependent self-degradation of VHL in different cell lines, in a highly isoform-selective fashion and without triggering a hy-poxic response. This approach offers a novel chemical probe for selective VHL knockdown, and demonstrates the potential for a new modality of chemical intervention on E3 ligases.
Original languageEnglish
Article number830
Pages (from-to)1-14
Number of pages14
JournalNature Communications
Publication statusPublished - 10 Oct 2017


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