Abstract 4869: Discovery and characterization of highly potent and selective USP7 inhibitors and benchmarking against clinical MDM2 antagonists

Given the importance of USP7 in known oncogenic pathways and its emerging role in immuno-oncology, the identification of USP7 inhibitors has attracted considerable interest in the scientific community. However, despite substantial efforts over the past 15 years, the development of genuine deubiquitinase (DUB) inhibitors, which exhibit both drug-like properties and a well-defined mechanism of action, has proven particularly challenging. In this study, we report the application of UbiPlexTM, our purpose-built DUB drug discovery platform, to USP7. In particular, we detail the identification, optimization and detailed characterization of a new class of non-covalent and highly potent USP7 inhibitors (IC50 < 10 nM). In addition, these inhibitors have shown exquisite selectivity for USP7 over other DUBs and proteases. We also disclose high-resolution co-crystal structures of USP7 in complex with these inhibitors that reveal an allosteric mode of binding. Further profiling in cells demonstrated potent target engagement with endogenous USP7 (EC50