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Deubiquitinase-targeting chimeras for targeted protein stabilization.
Nathaniel J Henning1,2,3, Lydia Boike1,2,3, Jessica N Spradlin1,2,3
1Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA.
Nature Chemical Biology
|February 25, 2022
Summary
Scientists developed deubiquitinase-targeting chimeras (DUBTACs) to stabilize proteins. This new therapeutic approach successfully stabilized cystic fibrosis transmembrane conductance regulator (CFTR) and WEE1 proteins, offering potential for treating various diseases.
Area of Science:
- Biochemistry
- Chemical Biology
- Drug Discovery
Background:
- Aberrant protein ubiquitination and degradation drive numerous diseases.
- Targeted protein stabilization (TPS) presents a promising therapeutic strategy for these conditions.
- Existing therapeutic modalities do not directly address protein degradation pathways.
Purpose of the Study:
- To introduce deubiquitinase-targeting chimeras (DUBTACs) as a novel platform for targeted protein stabilization.
- To discover covalent ligands that recruit deubiquitinases to specific protein targets.
- To demonstrate the therapeutic potential of DUBTACs in disease models.
Main Methods:
- Development of DUBTACs, heterobifunctional molecules linking deubiquitinase recruiters to protein-targeting ligands.
- Utilized chemoproteomic approaches to identify covalent ligands targeting deubiquitinases.
- Employed cell-based assays to assess protein stabilization and functional outcomes.
Main Results:
- Discovered EN523, a covalent ligand targeting the allosteric site of OTUB1.
- Constructed a DUBTAC using EN523 and lumacaftor to stabilize ΔF508-cystic fibrosis transmembrane conductance regulator (CFTR).
- Demonstrated robust stabilization of ΔF508-CFTR, improving chloride channel function in cystic fibrosis cells, and stabilized WEE1 in hepatoma cells.
Conclusions:
- DUBTACs represent a viable platform for targeted protein stabilization.
- Covalent chemoproteomic methods are effective for developing induced proximity-based therapeutics.
- This approach holds potential for treating diseases linked to protein degradation, including cystic fibrosis and cancer.
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