Molecular basis of USP7 inhibition by selective small-molecule inhibitors

Turnbull, A.P.; Ioannidis, Stephanos; Krajewski, Wojciech; Pinto-Fernández, Adán; Heride, Claire; Martin, Agnés C. L.; Tonkin, Louise M.; Townsend, Elizabeth; Buker, Shane M.; Lancia, David R.; Caravella, Justin A.; Toms, A.V.; Charlton, Thomas; Lahdenranta, Johanna; Wilker, Erik; Follows, Bruce; Evans, N.J.; Stead, Lucy F.; Alli, Cristina; Zarayskiy, Vladislav; Talbot, Adam C.; Buckmelter, Alexandre J.; Wang, Minghua; McKinnon, Crystal; Saab, Fabienne; McGouran, Joanna F.; Century, Hannah; Gersch, Malte; Pittman, Marc S.; Marshall, C. Gary; Raynham, Tony; Simcox, Mary Ellen; Stewart, Lorna; McLoughlin, Sheila B.; Escobedo, Jaime A.; Bair, Kenneth W.; Dinsmore, Christopher J.; Hammonds, Tim; Kim, Sunkyu; Urbé, Sylvie; Clague, Michael J.; Kessler, Benedikt M.; Komander, David

doi:10.1038/nature24451

Cited by 334 publications

(361 citation statements)

References 48 publications

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“…Although our data suggest that these DUBs could be playing a direct role in NLRP3 deubiquitination, we cannot rule out the possibility that USP47 and USP7 act on an upstream mediator of inflammasome activation and the precise mechanism of their contribution to inflammasome activation will need further study. There is already great interest in the development of USP7 inhibitors as therapeutic agents, especially in the field of oncology , and very selective USP7 inhibitors have been recently described . Given the new role of USP47 unveiled here, together with the known role for USP7 in immune pathways, dual USP7 and USP47 inhibitors could also become important for the treatment of inflammatory conditions in the future and, as our data suggest, would be fundamental in targeting inflammasome‐related pathologies.…”

Section: Discussionmentioning

confidence: 72%

USP7 and USP47 deubiquitinases regulate NLRP3 inflammasome activation

et al. 2018

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The assembly and activation of the inflammasomes are tightly regulated by post‐translational modifications, including ubiquitin. Deubiquitinases (DUBs) counteract the addition of ubiquitin and are essential regulators of immune signalling pathways, including those acting on the inflammasome. How DUBs control the assembly and activation of inflammasomes is unclear. Here, we show that the DUBs USP7 and USP47 regulate inflammasome activation in macrophages. Chemical inhibition of USP7 and USP47 blocks inflammasome formation, independently of transcription, by preventing ASC oligomerisation and speck formation. We also provide evidence that the ubiquitination status of NLRP3 itself is altered by inhibition of USP7 and USP47. Interestingly, we found that the activity of USP7 and USP47 increased in response to inflammasome activators. Using CRISPR/Cas9 in the macrophage cell line THP‐1, we show that inflammasome activation is reduced when both USP7 and USP47 are knocked down. Altogether, these data reveal a new post‐transcriptional role for USP47 and USP7 in inflammation by regulating inflammasome activation and the release of the pro‐inflammatory cytokines IL‐1β and IL‐18, and implicate dual USP7 and USP47 inhibitors as potential therapeutic agents for inflammatory disease.

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Section: Discussionmentioning

confidence: 72%

USP7 and USP47 deubiquitinases regulate NLRP3 inflammasome activation

et al. 2018

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“…Importantly, this work identified a new allosteric inhibitory site on USP7, implying that affinity-based screens rather than activity-based screens may reveal more druggable sites. Another group also used a similar approach to develop USP7 inhibitors with high potency (Turnbull et al, 2017). The work exemplified in these two studies is particularly relevant for producing compounds that are active against DUBs, where other methods have proven unsuccessful (Wrigley et al, 2011).…”

Section: Fragment-based Drug Discovery Of Potent and Specific Usp7 Inmentioning

confidence: 99%

Emerging drug development technologies targeting ubiquitination for cancer therapeutics

Veggiani

Gerpe

Sidhu

et al. 2019

Pharmacology & Therapeutics

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a b s t r a c t a r t i c l e i n f o Development of effective cancer therapeutic strategies relies on our ability to interfere with cellular processes that are dysregulated in tumors. Given the essential role of the ubiquitin proteasome system (UPS) in regulating a myriad of cellular processes, it is not surprising that malfunction of UPS components is implicated in numerous human diseases, including many types of cancer. The clinical success of proteasome inhibitors in treating multiple myeloma has further stimulated enthusiasm for targeting UPS proteins for pharmacological intervention in cancer treatment, particularly in the precision medicine era. Unfortunately, despite tremendous efforts, the paucity of potent and selective UPS inhibitors has severely hampered attempts to exploit the UPS for therapeutic benefits. To tackle this problem, many groups have been working on technology advancement to rapidly and effectively screen for potent and specific UPS modulators as intracellular probes or early-phase therapeutic agents. Here, we review several emerging technologies for developing chemical-and protein-based molecules to manipulate UPS enzymatic activity, with the aim of providing an overview of strategies available to target ubiquitination for cancer therapy.

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“…In order to establish molecular basis of USP7 inhibition, 2 compounds, FT671 and FT827, have been reported. Both compounds can bind to dynamic pocket near the catalytic center of apo‐USP7, and FT671 can regulate P53, P21, and MDM2 . In the past few years, increased interest has led to the identification of USP7 inhibitors that recently has started fulfilling the gap between perception and progression of new strategy.…”

Section: Ubiquitin Specific Protease 7 (Usp7)mentioning

confidence: 99%

Targeting ubiquitin specific protease 7 in cancer: A deubiquitinase with great prospects

Khusbu

Chen

2018

Cell Biochemistry & Function

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Deubiquitinase (DUB)-mediated cleavage of ubiquitin chain balances ubiquitination and deubiquitination for determining protein fate. USP7 is one of the best characterized DUBs and functionally important. Numerous proteins have been identified as potential substrates and binding partners of USP7; those play crucial roles in diverse array of cellular and biological processes including tumour suppression, cell cycle, DNA repair, chromatin remodelling, and epigenetic regulation. This review aims at summarizing the current knowledge of this wide association of USP7 with many cellular processes that enlightens the possibility of abnormal USP7 activity in promoting oncogenesis and the importance of identification of specific inhibitors.

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Molecular basis of USP7 inhibition by selective small-molecule inhibitors

Cited by 334 publications

References 48 publications

USP7 and USP47 deubiquitinases regulate NLRP3 inflammasome activation

USP7 and USP47 deubiquitinases regulate NLRP3 inflammasome activation

Emerging drug development technologies targeting ubiquitination for cancer therapeutics

Targeting ubiquitin specific protease 7 in cancer: A deubiquitinase with great prospects

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