2. Academic Validation
  3. Targeted degradation of USP7 in solid cancer cells reveals distinct effects of deubiquitinase degraders and inhibitors

Targeted degradation of USP7 in solid cancer cells reveals distinct effects of deubiquitinase degraders and inhibitors

  • Nat Commun. 2026 May 13;17(1):4331. doi: 10.1038/s41467-026-72295-x.
Nikolas Klink # 1 2,  Sebastian Urban # 3,  Johanna A Seier # 4,  Bikash Adhikari 5,  Martin P Schwalm 6 7,  Juliane Müller 5,  Madeleine Dorsch 3,  Philine Steinbach 4,  Jennifer Jung 3 8,  Markus Vogt 5,  Farnusch Kaschani 9,  Johannes Koch 10,  Siska Führer 1 2,  Markus Kaiser 11,  Nina Schulze 10,  Stefan Knapp 6 7 12,  Elmar Wolf 5,  Annette Paschen 13,  Barbara M Grüner 14 15,  Malte Gersch 16 17
Affiliations

Affiliations

  • 1 Department of Chemistry and Chemical Biology, TU Dortmund University, Dortmund, Germany.
  • 2 Max Planck Institute of Molecular Physiology, Dortmund, Germany.
  • 3 West German Cancer Center, Department of Medical Oncology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
  • 4 Department of Dermatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
  • 5 Institute of Biochemistry, University of Kiel, Kiel, Germany.
  • 6 Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Frankfurt am Main, Germany.
  • 7 Structural Genomics Consortium (SGC), Buchmann Institute for Molecular Life Sciences (BMLS), Frankfurt am Main, Germany.
  • 8 German Cancer Consortium, DKTK partner site Essen/Düsseldorf, a partnership between DKFZ and University Hospital Essen, University Duisburg-Essen, Essen, Germany.
  • 9 Faculty of Biology and Analytics Core Facility Essen (ACE), University of Duisburg-Essen, Essen, Germany.
  • 10 Imaging Center Campus Essen, Center of Medical Biotechnology, University of Duisburg-Essen, Essen, Germany.
  • 11 Faculty of Biology and Center of Medical Biotechnology, University of Duisburg-Essen, Essen, Germany.
  • 12 German Cancer Consortium, DKTK partner site Frankfurt-Mainz, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 13 Department of Dermatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. [email protected].
  • 14 West German Cancer Center, Department of Medical Oncology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. [email protected].
  • 15 German Cancer Consortium, DKTK partner site Essen/Düsseldorf, a partnership between DKFZ and University Hospital Essen, University Duisburg-Essen, Essen, Germany. [email protected].
  • 16 Department of Chemistry and Chemical Biology, TU Dortmund University, Dortmund, Germany. [email protected].
  • 17 Max Planck Institute of Molecular Physiology, Dortmund, Germany. [email protected].
  • # Contributed equally.
PMID: 42129197 DOI: 10.1038/s41467-026-72295-x
Abstract

Proteolysis-targeting chimeras (PROTACs) co-op the ubiquitin system for targeted protein degradation, creating opportunities to interrogate cellular functions of proteins through "chemical knockdown". However, matched pairs of protein degraders and inhibitors, that possess high specificity and chemical complementarity, for individual components of the ubiquitin system have remained scarce. This includes reagents to modulate activity and abundance of deubiquitinases (DUBs). Here, using an integrated chemical biology approach, we explore cellular functions of the DUB USP7 as a case study by comparing inhibition and degradation in melanoma and pancreatic Cancer cells. Through the synthesis of a degrader library, we identify and characterize potent USP7 PROTACs for each Cancer type. Proteomic and cellular analyses reveal that selective USP7 degradation modulates both shared and distinct protein sets across both cancers without affecting cell growth. In contrast, prolonged inhibitor treatment induces USP7-independent proteomic and metabolic dysregulation, highlighting important caveats for the cellular use of hydroxypiperidine-based USP7 inhibitors. Collectively, our work provides a comprehensively characterized chemical toolbox to distinguish on-target phenotypes which will aid the understanding of USP7 in malignant diseases. More broadly, our data emphasize the importance of increased specificity via PROTAC-mediated degradation and the potential of this modality to elucidate cell-line specific functions of DUBs.

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