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

Sep 22, 2026

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Proteolysis-targeting chimeras (PROTACs) enable targeted protein degradation via the ubiquitin-proteasome system, but matched inhibitor–degrader pairs for deubiquitinases have remained limited. Using an integrated chemical biology strategy, the study compares inhibition versus degradation of the DUB USP7 in melanoma and pancreatic cancer cells. A degrader library identifies potent USP7 PROTACs, and proteomic plus cellular analyses show selective USP7 degradation alters shared and distinct protein sets without affecting growth. In contrast, prolonged inhibitor treatment causes USP7-independent proteomic and metabolic dysregulation, underscoring caveats for hydroxypiperidine-based inhibitors.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages18

Reading Time45 min

AccessFree to download

Background

PROTACs and limitations of matched pairs

Deubiquitinases and therapeutic relevance

Why USP7 is a suitable case study

Study approach and rationale

Degrader library synthesis

Comparative analyses: degradation vs inhibition

Article [https://doi.org/10.1038/s41467-026-72295-x](https://doi.org/10.1038/s41467-026-72295-x) Targeted degradation of USP7 in solid cancer cells reveals distinct effects ofdeubiquitinasedegraders and inhibitors Received: 3 July 2025 | Accepted: 14 April 2026 | | --- | | | | Check for updates | Nikolas Klink 1,2,13, Sebastian Urban3,13, Johanna A. Seier4,13, Bikash Adhikari 5, Martin P. Schwalm 6,7, Juliane Müller5, Madeleine Dorsch3, Philine Steinbach4, 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 4 , Barbara M. Grüner 3,8 & Malte Gersch 1,2 Proteolysis-targeting chimeras (PROTACs) co-op the ubiquitin system for targeted protein degradation, creating opportunities to interrogate cellular functions ofproteins 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 ofa 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. Proteolysis-targeting chimeras (PROTACs) have emerged as powerful tools for both therapeutic applications and mechanistic biology. These hetero-bifunctional molecules enable rapid targeted protein degradation by hijacking the endogenous ubiquitin-proteasome system and have demonstrated remarkable potential in overcoming some of the limitations associated with conventional small molecule inhibitors1,2. Moreover, comparative studies assessing effects of targeted protein degradation vs. protein inhibition have revealed distinct outcomes facilitated by both modalities (e.g., for the transcriptional regulator BRD4)3–5 A full list of afﬁliations appears at the end of the paper. e-mail: [annette.paschen@uk-essen.de](annette.paschen@uk-essen.de); [barbara.gruener@uk-essen.de](barbara.gruener@uk-essen.de); [malte.gersch@tu-dortmund.de](malte.gersch@tu-dortmund.de) and enabled the discovery of non-catalytic protein functions (e.g., for the kinase Aurora A)6,7. However, such comparative analyses require matched pairs of well-characterized inhibitors and degraders, a requirement that remains largely unmet across most protein families. The around 100 human deubiquitinating enzymes (DUBs) act as counterplayers of over 600 E3 ligases and represent a particularly compelling yet underexplored class of proteins where matched pairs of inhibitors and degraders are urgently needed8,9. These enzymes serve as critical regulators of cellular protein homeostasis and ubiquitin-mediated signaling. DUBs have emerged as promising therapeutic targets in cancer, neurodegeneration, and inﬂammatory disorders10. Despite their therapeutic potential, the development of selective DUB modulators has been challenging which has also hampered investigations into their cel

FAQs

What does the study compare to understand USP7 function in cancer cells?

It compares USP7 inhibition with USP7 targeted degradation using PROTACs in melanoma and pancreatic cancer cells, focusing on how each modality changes cellular protein behavior.

How were potent USP7 PROTACs identified in the research?

The work synthesizes a degrader library and then identifies and characterizes potent USP7 PROTACs specific to each cancer type.

Why do inhibitor and degrader treatments lead to different proteomic and metabolic outcomes?

Selective USP7 degradation modulates specific protein sets without affecting growth, while prolonged inhibitor treatment induces USP7-independent proteomic and metabolic dysregulation, indicating important limitations of the inhibitor class studied.

Sep 22, 2026

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