Chemically Induced Degradation of Native Proteins by Direct Recruitment to the 26S Proteasome

Abstract Targeted protein degradation (TPD) is a promising strategy for drug development. Most degraders function by forcing the association of the target protein (TP) with an E3 Ubiquitin ligase, which in favorable cases results in the poly-Ubiquitylation of the TP and its subsequent degradation by the 26S proteasome. Here we explore the feasibility of a different TPD strategy in which the TP is recruited directly to the proteasome without the requirement for poly-Ubiquitylation. Using an engineered cell line in which the HaloTag protein is fused to one of the Ubiquitin receptors, we show that native protein targets can be degraded in this fashion when the cells are exposed to a chemical dimerizer containing a chloroalkane and a TP ligand. The potential advantages and disadvantages of Ubiquitin-independent degraders vs. traditional proteolysis-targeting chimeras are discussed.