ByeTAC: Bypassing E-Ligase-Targeting Chimeras for Direct Proteasome Degradation

J Med Chem. 2025 May 8;68(9):9694-9705. doi: 10.1021/acs.jmedchem.5c00485. Epub 2025 Apr 19.

Abstract

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.

MeSH terms

  • Humans
  • Ligands
  • Proteasome Endopeptidase Complex* / metabolism
  • Proteolysis*
  • Ubiquitin-Protein Ligases* / metabolism
  • Ubiquitination

Substances

  • Proteasome Endopeptidase Complex
  • Ubiquitin-Protein Ligases
  • ATP dependent 26S protease
  • 26S proteasome non-ATPase regulatory subunit 13
  • Ligands