Jennifer A. Ward, Adan Pinto-Fernandez, Loic Cornelissen, Sarah Bonham, Laura Díaz-Sáez, Olivier Riant, Kilian V. M. Huber, Benedikt M Kessler, Olivier Feron, and Edward W. Tate
Journal of Medicinal Chemistry 2020
DOI: 10.1021/acs.jmedchem.0c00144
Deubiquitinating enzymes are a growing target class across multiple disease states, with several inhibitors now report-ed. 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 complexes. Activity-based proteome profiling identified CIAPIN1 as a sub-micromolar covalent target of VLX1570, and further analysis demonstrated that high molecular weight complex formation leads to aggregation of CIAPIN1 in intact cells. Our results suggest that in addition to DUB inhibition, these compounds induce non-specific protein aggregation, providing a molecular explanation for general cellular toxicity.
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