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. 2025 Oct 21;122(42):e2510496122.
doi: 10.1073/pnas.2510496122. Epub 2025 Oct 14.

Small-molecule allosteric activator of ubiquitin-specific protease 7 (USP7)

Isabella Jaen Maisonet #  1   2 , Mona Sharafi #  1   2 , Emilie J Korchak  3 , Andres Salazar-Chaparro  1   2 , Ariana S Bratt  1   2 , Tvesha Parikh  3 , Anthony C Varca  1   2 , Binita Shah  1   2 , Michael Darnowski  1   2 , Mia Chung  1   2 , Wei Pin Teh  1   2 , Jianwei Che  1   2 , Irina Bezsonova  3 , Sara J Buhrlage  1   2
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Small-molecule allosteric activator of ubiquitin-specific protease 7 (USP7)

Isabella Jaen Maisonet et al. Proc Natl Acad Sci U S A. .

Abstract

Ubiquitin-specific protease 7 (USP7) is a deubiquitylase essential for cell homeostasis, DNA repair, and regulation of both tumor suppressors and oncogenes. Recently, haploinsufficiency of USP7 has 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, USP7 activators may represent a more relevant approach. To address this challenge, we report the identification and characterization of a small-molecule activator of USP7 called MS-8. Structural and functional studies show that MS-8 allosterically activates USP7, mimicking the endogenous autoactivation mechanism of the enzyme. 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 toward activation-driven USP7 pharmacology.

Keywords: DUB; Hao–Fountain syndrome; USP7; deubiquitylases; small-molecule activator.

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Conflict of interest statement

Competing interests statement:S.J.B. is a founder, SAB member, and equity holder of Entact Bio and receives or has received sponsored research funding from Novartis Institutes for BioMedical Research, AbbVie, Kinogen, TUO Therapeutics, Takeda, and Pivotal Life Sciences. I.J.M., M.S., S.J.B., and I.B. are named inventors on a patent related to this work.

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