Targeted Degradation of Histone Deacetylases via Bypassing E3 Ligase Targeting Chimeras (BYETACs)

Targeted protein degradation (TPD) through heterobifunctional molecules to initiate ubiquitination and facilitate subsequent degradation has emerged as a powerful therapeutic strategy. Most heterobifunctional molecules designed for TPD function primarily through a limited set of E3 ligases, which restricts this therapeutic approach to specific tissues that express the necessary ligases. Herein, we have developed a novel series of heterobifunctional bypassing E3 targeting chimeras (BYETACs) for the targeted degradation of histone deacetylases (HDACs). To this end, a ubiquitin-specific protease 14 (USP14) inhibitor is utilized for the first time as a novel ligand that can directly bind to the 26S proteasome subunit RPN1. Subsequent conjugation of the USP14 ligand with the HDAC inhibitor vorinostat yielded HDAC BYETACs that effectively and preferentially reduced HDAC1 protein levels in multiple myeloma MM.1S cells.