Nomura DK.
*
et al.
University of California, Novartis-Berkeley Center for Proteomics and Chemistry Technologies and Innovative Genomics Institute, Berkeley, USA
Deubiquitinase-Targeting Chimeras for Targeted Protein Stabilization.
Nat. Chem. Biol. 2022;
18: 412-421
DOI:
10.1038/s41589-022-00971-2
Key words
DUBTACs - targeted protein stabilization - Ullmann coupling
Significance
Irregular protein degradation plays a critical role in the pathogenesis of many diseases, such as cystic fibrosis and several forms of cancer. Thus, targeted protein stabilization (TPS) offers a novel therapeutic strategy for such cases. Utilizing an approach analogous to proteolysis-targeting chimeras (PROTACs), Nomura and co-workers developed deubiquitinase-targeting chimeras (DUBTACs) as small-molecule recruiters of the deubiquitinase OTUB1 to stabilize polyubiquitinated proteins of interest tagged for proteasomal degradation.
Comment
Using chemoproteomics, Nomura and co-workers identified OTBU1 as an ideal candidate for recruitment and demonstrated acrylamide EN523 be a selective ligand for OTBU1 with no loss of activity. DUBTAC NJH-2-057 was generated by linking EN523 to the pharmaceutical drug lumacaftor to target mutant chloride channel ΔF508-CFTR, the degradation of which is associated with the cystic fibrosis phenotype. In vitro assays demonstrated a dose-dependent and time-responsive restoration of CFTR levels and function, justifying further investigations into DUBTAC-mediated TPS.
