Application of targeted protein degradation strategies to deubiquitinating enzymes (DUBs)

PROTACs (Proteolysis Targeting Chimeras) have emerged as an important method of achieving TPD. PROTACs are bifunctional molecules which consist of a POI binder and an E3 ligase binder joined via a linker which enable a ternary complex to form between the POI and E3 leading to ubiquitination and subsequent degradation. <br><br>In this work, targeted protein degradation strategies have been applied to DUBs as a therapeutic strategy.

To this end, a range of PROTACs were synthesised using proprietary DUB-inhibitor recruiters against three DUB targets (USP1, USP7 and USP15) and evaluated in various cellular assays including chemo-proteomic analysis. From this work, lead PROTACs have been identified which show rapid degradation of USP15 with a long-lasting effect and the mechanism of action was confirmed to be through the proteasome. This provides a valuable tool to further probe USP15 biology and allow investigation into the effects of target degradation in disease relevant models. <br><br><i>Thesis is embargoed until 31st July 2028</i>.