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Deubiquitinases are important components of the protein regulatory network and, hence, constitute a tempting drug target. We report herein structure-activity relationship studies to develop halogen-substituted isoquionoline-1,3-dione-based inhibitors of the deubiquitinase USP2. In contrast to our previous reports, the best compound discovered was found to act through a reactive oxygen species independent, uncompetitive mechanism with an IC50 of 250 nm. We show the crucial role of halogens in the common scaffold to provide potency and selectivity of our compound, where the introduction of the fluorine atom completely switches the selectivity of the inhibitor between USP2 and USP7. Our cellular studies highlight the potential applicability of the reported compound for in vivo experiments. The discovery of the isoquinoline-1,3-dione core and the knowledge obtained with regard to halogen substituents provide a platform towards understanding USP2 inhibition and the development of highly selective next-generation deubiquitinase inhibitors.

SIRT1 specificity: The multispecific SIRT1 enzyme catalyzes the deacetylation of acetyllysine residues within protein targets. However, little is known regarding the molecular basis for SIRT1 substrate recognition. Kinetic analysis of SIRT1 with a panel of peptide substrates shows the high importance of the region N-flanking the target acetyllysine and its high conservation through evolution.