1. Academic Validation
  2. Homo-PROTACs: bivalent small-molecule dimerizers of the VHL E3 ubiquitin ligase to induce self-degradation

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

  • Nat Commun. 2017 Oct 10;8(1):830. doi: 10.1038/s41467-017-00954-1.
Chiara Maniaci 1 2 Scott J Hughes 1 Andrea Testa 1 Wenzhang Chen 1 Douglas J Lamont 1 Sonia Rocha 3 Dario R Alessi 2 Roberto Romeo 4 Alessio Ciulli 5
Affiliations

Affiliations

  • 1 Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, James Black Centre, Dow Street, Dundee, Scotland, DD1 5EH, UK.
  • 2 Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, James Black Centre, Dow Street, Dundee, Scotland, DD1 5EH, UK.
  • 3 Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, James Black Centre, Dow Street, Dundee, DD1 5EH, Scotland, UK.
  • 4 Dipartimento di Scienze Chimiche, Biologiche, Farmaceutiche ed Ambientali, University of Messina, Polo Universitario Viale SS. Annunziata SNC, Messina, 98168, Italy.
  • 5 Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, James Black Centre, Dow Street, Dundee, Scotland, DD1 5EH, UK. [email protected].
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 importance 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 hypoxic 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.Targeting the ubiquitin Proteasome system to modulate protein homeostasis using small molecules has promising therapeutic potential. Here the authors describe Homo-PROTACS: small molecules that can induce the homo-dimerization of E3 ubiquitin ligases and cause their proteasome-dependent degradation.

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