Targeting the spliceosomal protein USP39 through allosteric ligands and PROTAC-induced degradation

In a new publication in Angewandte Chemie PROXIDRUGS member Xinlai Cheng and researchers from Goethe University Frankfurt, Max Planck Institute of Biophysics and Ludwig Maximilian University Munich have reported an important advance in targeted protein degradation by developing a potent degraders (PROTACs) against the spliceosomal protein USP39.

RNA splicing is essential for gene expression, and its dysregulation is strongly linked to cancer and neurodegenerative disorders. USP39 plays a critical structural role within this process but lacks enzymatic activity, making it a particularly challenging target for classical drug discovery approaches.

To overcome this hurdle, the team identified ligands that selectively bind the zinc finger domain of USP39. Using AlphaFold-guided modeling, these ligands were successfully converted into PROTAC degraders. The lead compound, USP39_PROTAC_V1, recruits the VHL E3 ligase and induces highly efficient degradation of USP39 at concentrations as low as 1 nM, while showing high selectivity across the proteome and litte off-target effects. Mechanistic studies confirmed that degradation is dependent on VHL engagement and linked to proteosomal activity. USP39 degradation reproduced characteristic splice-site defects previously linked to splicing-associated disease pathways, highlighting USP39 as a promising therapeutic entry point for conditions such as cancer and retinitis pigmentosa.

Overall, this work demonstrates how chemically induced proximity and PROTAC technology can enable efficient degradation of traditionally undruggable targets like USP39, expanding future therapeutic opportunities beyond conventional drug discovery approaches.

Link to publication

Graphical Abstract - Angew. Chem. Int. Ed. 2026, 65, e16809: Proteolysis-targeting chimeras (PROTACs) enable degradation of proteins previously considered undruggable by harnessing the cellular ubiquitin–proteasome system. In this study, Schäfer et al. identify thiazole-based small molecules that allosterically bind the zinc finger domain of ubiquitin-specific protease 39 (USP39), a non-enzymatic scaffold protein essential for spliceosome assembly and implicated in proteotoxicity-relevant diseases. These ligands were converted into PROTACs that effectively recruit E3 ligases, induce potent, selective USP39 degradation at nanomolar concentrations in cells.