Cereblon versus VHL: Hijacking E3 ligases against each other using PROTACs.
Cereblon
E3 ubiquitin ligases
PROTACs
Targeted protein degradation
von Hippel-Lindau protein
Journal
Bioorganic & medicinal chemistry
ISSN: 1464-3391
Titre abrégé: Bioorg Med Chem
Pays: England
ID NLM: 9413298
Informations de publication
Date de publication:
15 06 2019
15 06 2019
Historique:
received:
01
02
2019
revised:
19
02
2019
accepted:
21
02
2019
pubmed:
4
3
2019
medline:
9
9
2020
entrez:
4
3
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 30826187
pii: S0968-0896(19)30172-5
doi: 10.1016/j.bmc.2019.02.048
pmc: PMC6561380
pii:
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
CRBN protein, human
0
Imidazoles
0
Ligands
0
Ubiquitin-Protein Ligases
EC 2.3.2.27
Von Hippel-Lindau Tumor Suppressor Protein
EC 2.3.2.27
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2466-2479Subventions
Organisme : Wellcome Trust
ID : 094090/Z/10/Z
Pays : United Kingdom
Informations de copyright
Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.
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