Cereblon versus VHL: Hijacking E3 ligases against each other using PROTACs

Miriam Girardini, Chiara Maniaci, Scott Hughes, Andrea Testa, Alessio Ciulli (Lead / Corresponding author)

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)2466-2479
Number of pages14
JournalBioorganic & Medicinal Chemistry
Volume27
Issue number12
Early online date22 Feb 2019
DOIs
Publication statusPublished - 15 Jun 2019

Fingerprint

Proteolysis
Ubiquitin-Protein Ligases
Degradation
Cullin Proteins
Ubiquitination
Proteins
Cells
Cell Line
Substrates
Neoplasms

Keywords

  • Cereblon
  • E3 ubiquitin ligases
  • PROTACs
  • Targeted protein degradation
  • von Hippel-Lindau protein

Cite this

@article{199369dac860479ca36a26de3eba2572,
title = "Cereblon versus VHL: Hijacking E3 ligases against each other using PROTACs",
abstract = "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.",
keywords = "Cereblon, E3 ubiquitin ligases, PROTACs, Targeted protein degradation, von Hippel-Lindau protein",
author = "Miriam Girardini and Chiara Maniaci and Scott Hughes and Andrea Testa and Alessio Ciulli",
note = "This project has received funding from the European Research Council (ERC) under the European Union’s Seventh Framework Programme (FP7/2007−2013) as a Starting Grant to A.C. (grant agreement no. ERC-2012-StG-311460 DrugE3CRLs). Drug discovery activities were supported by Wellcome Trust strategic awards to Dundee (094090/Z/10/Z). M.G. and C.M. were funded by PhD Studentships from the Italian Ministry of Education, University and Research (Miur). We thank S. Imaide for the gift of linker intermediates.",
year = "2019",
month = "6",
day = "15",
doi = "10.1016/j.bmc.2019.02.048",
language = "English",
volume = "27",
pages = "2466--2479",
journal = "Bioorganic & Medicinal Chemistry",
issn = "0968-0896",
publisher = "Elsevier",
number = "12",

}

TY - JOUR

T1 - Cereblon versus VHL

T2 - Hijacking E3 ligases against each other using PROTACs

AU - Girardini, Miriam

AU - Maniaci, Chiara

AU - Hughes, Scott

AU - Testa, Andrea

AU - Ciulli, Alessio

N1 - This project has received funding from the European Research Council (ERC) under the European Union’s Seventh Framework Programme (FP7/2007−2013) as a Starting Grant to A.C. (grant agreement no. ERC-2012-StG-311460 DrugE3CRLs). Drug discovery activities were supported by Wellcome Trust strategic awards to Dundee (094090/Z/10/Z). M.G. and C.M. were funded by PhD Studentships from the Italian Ministry of Education, University and Research (Miur). We thank S. Imaide for the gift of linker intermediates.

PY - 2019/6/15

Y1 - 2019/6/15

N2 - 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.

AB - 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.

KW - Cereblon

KW - E3 ubiquitin ligases

KW - PROTACs

KW - Targeted protein degradation

KW - von Hippel-Lindau protein

UR - http://www.scopus.com/inward/record.url?scp=85062045136&partnerID=8YFLogxK

U2 - 10.1016/j.bmc.2019.02.048

DO - 10.1016/j.bmc.2019.02.048

M3 - Article

C2 - 30826187

VL - 27

SP - 2466

EP - 2479

JO - Bioorganic & Medicinal Chemistry

JF - Bioorganic & Medicinal Chemistry

SN - 0968-0896

IS - 12

ER -