Synthesis and Evaluation of Cereblon-Recruiting HaloPROTACs

Target validation is key to the development of protein degrading molecules such as proteolysis-targeting chimeras (PROTACs) to identify cellular proteins amenable for induced degradation by the ubiquitin-proteasome system (UPS). Previously the HaloPROTAC system was developed to screen targets of PRO...

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Published inChembiochem : a European journal of chemical biology Vol. 24; no. 21; p. e202300498
Main Authors Ody, Britton K., Zhang, Jing, Nelson, Sydney E., Xie, Yayun, Liu, Ruochuan, Dodd, Cayden J., Jacobs, Savannah E., Whitzel, Savannah L., Williams, Leighan A., Gozem, Samer, Turlington, Mark, Yin, Jun
Format Journal Article
LanguageEnglish
Published WEINHEIM Wiley 02.11.2023
Wiley Subscription Services, Inc
Subjects
Biochemistry & Molecular Biology
Biodegradation
Chemistry, Medicinal
Chimeras
Degradation
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Proteasomes
Proteins
Proteolysis
Science & Technology
Ubiquitin
Ubiquitination
UBIQUITINATION
HaloPROTAC
HaloTag
DESIGN
Cereblon
PROTAC
HYBRID MOLECULES
PROTACS
TARGETED PROTEIN-DEGRADATION
KNOCKDOWN
ubiquitin
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Summary:Target validation is key to the development of protein degrading molecules such as proteolysis-targeting chimeras (PROTACs) to identify cellular proteins amenable for induced degradation by the ubiquitin-proteasome system (UPS). Previously the HaloPROTAC system was developed to screen targets of PROTACs by linking the chlorohexyl group with the ligands of E3 ubiquitin ligases VHL and cIAP1 to recruit target proteins fused to the HaloTag for E3-catalyzed ubiquitination. Reported here are HaloPROTACs that engage the cereblon (CRBN) E3 to ubiquitinate and degrade HaloTagged proteins. A focused library of CRBN-pairing HaloPROTACs was synthesized and screened to identify efficient degraders of EGFP-HaloTag fusion with higher activities than VHL-engaging HaloPROTACs at sub-micromolar concentrations of the compound. The CRBN-engaging HaloPROTACs broadens the scope of the E3 ubiquitin ligases that can be utilized to screen suitable targets for induced protein degradation in the cell. A bifunctional HaloPROTAC ligand was developed to recruit the CRBN E3 ubiquitin ligase to degrade target proteins fused with a HaloTag in the cell. The CRBN-recruiting HaloPROTAC can expand the use of the HaloPROTAC system for screening the degradation targets for therapeutic discovery.+image
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ISSN:1439-4227
1439-7633
DOI:10.1002/cbic.202300498