TY - JOUR
T1 - Cereblon versus VHL
T2 - Hijacking E3 ligases against each other using PROTACs
AU - Girardini, Miriam
AU - Maniaci, Chiara
AU - Hughes, Scott J.
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 -
