Small-molecule allosteric activator of ubiquitin-specific protease 7 (USP7)
Jaen Maisonet, I.; Sharafi, M.; Korchak, E. J.; Salazar-Chaparro, A.; Bratt, A.; Parikh, T.; Varca, A. C.; Shah, B.; Darnowski, M.; Chung, M.; Teh, W. P.; Che, J.; Bezsonova, I.; Buhrlage, S. J.
Show abstract
Ubiquitin-specific protease 7 (USP7) is a deubiquitylase essential for cell homeostasis, DNA repair, and regulation of both tumor suppressors and oncogenes. Inactivating USP7 mutations have been associated with Hao-Fountain Syndrome (HAFOUS), a rare neurodevelopmental disorder. Although a range of USP7 inhibitors have been developed over the last decade, in the context of HAFOUS as well as oncogene regulation, USP7 activators may represent a more relevant approach. To address this challenge, we report the discovery and characterization of a small-molecule activator of USP7 called MS-8. We showed that MS-8 activates USP7 by engaging the allosteric C-terminal binding pocket of USP7, thus mimicking the allosteric autoactivation by the USP7 C-terminal tail. We observed that MS-8 engages and activates mutant USP7 in a cellular context, impacting downstream proteins. Taken together, our study provides validation of the USP7 activator that paves the way towards novel activation-driven USP7 pharmacology.
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