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.

doi:10.1101/2025.03.14.643379

bioRxiv · 10.1101/2025.03.14.643379

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.

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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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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.. 2025-03-16. Small-molecule allosteric activator of ubiquitin-specific protease 7 (USP7). https://doi.org/10.1101/2025.03.14.643379

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