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

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.