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.