The Ubiquitin-Proteasome System is a popular drug target. Proteasome inhibitors have been widely applied in treating cancers and autoimmune diseases, while activators of the proteasome have shown preliminary efficacy in animal models of neurodegenerative diseases. The recent development of Proteolysis Targeting Chimera (PROTAC) compounds enables selective degradation of protein-of-interest and has triggered strong enthusiasm in targeting multiple diseases.
Widely-used proteasome reporters detect the 20S activity which is not closely associated with proteasome’s primary function of degrading ubiquitylated proteins. In a previous study, we developed a novel reporter system that can accurately measure the ubiquitin-dependent activity of the 26S proteasome both in vitro and in vivo. We developed drug screening platforms based on these reporters to explore the pharmacological space for modulating the proteasomal activities. In an unpublished study, we identified novel modulators of the ubiquitin-proteasome system which may boost the efficacy of the proteolysis-targeting drugs.
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