The post-translational modification of proteins by ubiquitin mediates the concentration or activity of a large fraction of the proteome by impacting proteasomal and lysosomal degradation, localization, complexation, and susceptibility to other post-translational modification. Deubiquitinating enzymes (DUBs) are a family of more than 100 proteases that catalyze the removal of ubiquitin from substrate proteins (Figure 1a). As a result, DUBs perform key roles in virtually all normal physiology and human disease. In cancer, for example, USP6 fusion genes contribute to malignancy in aneurysmal bone cysts, while USP7 and USP8 stabilize oncogenic proteins HDM2 and mutant EGFR, respectively. DUBs have been linked to neurodegeneration through roles in regulating mitophagy, autophagy and acting directly on protein aggregates. Despite intense interest in their function and potential as therapeutic targets, there are few selective small molecule probes for DUBs and no approved DUB-targeting drugs. We have built a platform for developing and validating DUB inhibitors that includes library synthesis and medicinal chemistry, biochemistry and screening, chemical proteomics, structural biology, and cancer biology. This platform has enabled us to assemble DUB-targeted libraries annotated for selectivity across the gene family that have proven powerful in linking target and phenotype across multiple projects. In one example, the dataset revealed a highly selective inhibitor for USP7 that was subsequently optimized and utilized to pharmacologically interrogate reported functions of USP7 (Figure 1b). In a different type of example, we performed a cellular phenotypic screen of the annotated DUB inhibitor library to identify compounds that could induce degradation of oncogenic FLT3. Subsequent target deconvolution efforts allowed us to identify USP10 as the critical DUB required to stabilize FLT3.

Target class platform accelerates deubiquitinase early discovery efforts

256th National Meeting (2018)

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