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)

Research output: Contribution to journalArticlepeer-review

74 Citations (Scopus)
199 Downloads (Pure)

Abstract

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
Volume8
DOIs
Publication statusPublished - 10 Oct 2017

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