2025/04/19 by Cody A. Loy, Eslam M.H. Ali, Laurence J. Seabrook +4 · 1 voice
Biochemistry, Genetics and Molecular Biology · #Histone Deacetylase Inhibitors Research #Protein Degradation and Inhibitors #Ubiquitin and proteasome pathways
paper · doi:10.1021/acs.jmedchem.5c00485
openalex publication_date 2025/04/19 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/28
The development of targeted protein degradation by recruiting a protein of interest to a ubiquitin ligase to facilitate its degradation has become a powerful therapeutic tool. The potential of this approach is limited to proteins that can be readily ubiquitinated and relies on having a ligand with the various E3 ligases. Here, we describe a new methodology for targeted protein degradation that directly recruits a protein of interest to the proteasome for degradation. We generated bifunctional molecules that incorporate a small molecule ligand into a subunit on the 26S proteasome that recruits the protein directly for degradation. ByeTAC degradation requires binding to Rpn-13, a nonessential ubiquitin receptor of the 26S proteasome, and the protein of interest and does not have to rely on the E ligase cascade for ubiquitination. The ByeTAC methodology demonstrates the application of directly recruiting a protein to the proteasome via interactions with Rpn-13 for degradation.