期刊
CHEMISTRY & BIOLOGY
卷 18, 期 11, 页码 1401-1412出版社
CELL PRESS
DOI: 10.1016/j.chembiol.2011.08.018
关键词
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资金
- Swedish Research Council
- Loo and Hans Osterrnans Foundation for Geriatric Research
- Foundation for Geriatric Diseases at Karolinska Institutet
- Biomedical Research Centre (NIHR), Oxford, UK
- Action Medical Research Grant
- Computational Biology Research Group (CBRG), Oxford, UK
- MRC [MC_U142762994, G0501068] Funding Source: UKRI
- Medical Research Council [G0501068, MC_U142762994] Funding Source: researchfish
Converting lead compounds into drug candidates is a crucial step in drug development, requiring early assessment of potency, selectivity, and off-target effects. WE: have utilized activity-based chemical proteomics to determine the potency and selectivity of deubiquitylating enzyme (DUB) inhibitors in cell culture models. Importantly, we characterized the small molecule PR-619 as a broad-range DUB inhibitor, and P22077 as a USP7 inhibitor with potential for further development as a chemotherapeutic agent in cancer therapy. A striking accumulation of polyubiquitylated proteins was observed after both selective and general inhibition of cellular DUB activity without direct impairment of proteasomal proteolysis. The repertoire of ubiquitylated substrates was analyzed by tandem mass spectrometry, identifying distinct subsets for general or specific inhibition of DUBs. This enabled identification of previously unknown functional links between USP7 and enzymes involved in DNA repair.
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