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Quantitative Chemical Proteomic Profiling of Ubiquitin Specific Proteases in Intact Cancer Cells

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posted on 25.10.2016, 00:00 by Jennifer A. Ward, Lauren McLellan, Martin Stockley, Karl R. Gibson, Gavin A. Whitlock, Charlotte Knights, Jeanine A. Harrigan, Xavier Jacq, Edward W. Tate
Deubiquitinating enzymes play an important role in a plethora of therapeutically relevant processes and are emerging as pioneering drug targets. Herein, we present a novel probe, Ubiquitin Specific Protease (USP) inhibitor, alongside an alkyne-tagged activity-based probe analogue. Activity-based proteome profiling identified 12 USPs, including USP4, USP16, and USP33, as inhibitor targets using submicromolar probe concentrations. This represents the first intact cell activity-based profiling of deubiquitinating enzymes. Further analysis demonstrated functional inhibition of USP33 and identified a synergistic relationship in combination with ATR inhibition, consistent with USP4 inhibition.

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