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

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.

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Publication Details

Journal
Proceedings of the National Academy of Sciences
Published
2025-10-14
DOI
https://doi.org/10.1073/pnas.2510496122
Citations
1
Primary Topic
Ubiquitin and proteasome pathways
Type
article
Field-Weighted Citation Impact
0.81
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article

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

Michael G. Darnowski, Ariana S. Bratt, Mona Sharafi, Binita Shah et al.
1 citations
Proceedings of the National Academy of Sciences
Ubiquitin and proteasome pathways
0.81
article

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

Michael G. Darnowski, Ariana S. Bratt, Mona Sharafi, Binita Shah, Andres Salazar‐Chaparro, Irina Bezsonova, Anthony C. Varca, Sara J. Buhrlage, Mia Chung, Jianwei Che, Toral Parikh, Isabella Jaen Maisonet, Wei Pin Teh, Emilie J. Korchak
article en
1 citations

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.

Proceedings of the National Academy of SciencesVol. 122(42)
Harvard University (US), University of Connecticut (US), Boston VA Research Institute (US), Dana-Farber Cancer Institute (US), Institute of Molecular Biology and Biophysics (RU), UConn Health (US)
Openalex Percentile: Top 23%
Ubiquitin and proteasome pathways
0.81
DOIOpen Access PDFOpenAlex
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