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Deubiquitinating enzymes (DUBs) are a growing target class across multiple disease states, with several inhibitors now reported. b-AP15 and VLX1570 are two structurally related USP14/UCH-37 inhibitors. Through a proteomic approach, we demonstrate that these compounds target a diverse range of proteins, resulting in the formation of higher molecular weight (MW) complexes. Activity-based proteome profiling identified CIAPIN1 as a submicromolar covalent target of VLX1570, and further analysis demonstrated that high MW complex formation leads to aggregation of CIAPIN1 in intact cells. Our results suggest that in addition to DUB inhibition, these compounds induce nonspecific protein aggregation, providing molecular explanation for general cellular toxicity.

Original publication




Working paper

Publication Date





3756 - 3762


Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, U.K.


Cell Line, Tumor, Humans, Benzylidene Compounds, Azepines, Piperidones, Intracellular Signaling Peptides and Proteins, Proteome, Enzyme Inhibitors, Cross-Linking Reagents, Proteomics, Protein Multimerization, Deubiquitinating Enzymes