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 UbiPlex TM , 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 (IC 50 Further profiling in cells demonstrated potent target engagement with endogenous USP7 (EC 50 50 In summary, this work exemplifies the tractability and druggability of USP7 as a cancer target and provides new insights and directions for the potential clinical development of USP7 inhibitors. Citation Format: Gerald Gavory, Colin O9Dowd, Elias Arkoudis, Oliver Barker, Eamon Cassidy, Anthony Dossang, Jakub Flasz, Matt Helm, Caroline Hughes, Keeva McClelland, Hugues Miel, Ewa Odrzywol, Natalie Page, Tim Harrison. Discovery and characterization of highly potent and selective USP7 inhibitors and benchmarking against clinical MDM2 antagonists [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4869.