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@article{Conole:2023:10.1002/anie.202311190,
author = {Conole, D and Cao, F and Am, Ende CW and Xue, L and Kantesaria, S and Kang, D and Jin, J and Owen, D and Lohr, L and Schenone, M and Majmudar, JD and Tate, EW},
doi = {10.1002/anie.202311190},
journal = {Angewandte Chemie International Edition},
title = {Discovery of a potent deubiquitinase (DUB) small molecule activitybased probe enables broad spectrum DUB activity profiling in living cells},
url = {http://dx.doi.org/10.1002/anie.202311190},
volume = {62},
year = {2023}
}

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TY  - JOUR
AB  - Deubiquitinases (DUBs) are a family of >100 proteases that hydrolyze isopeptide bonds linking ubiquitin to protein substrates. This leads to reduced substrate degradation through the ubiquitin proteasome system. Deregulation of DUB activity has been implicated in many diseases, including cancer, neurodegeneration and auto-inflammation, and several have been recognized as attractive targets for therapeutic intervention. Ubiquitin-derived covalent activity-based probes (ABPs) provide a powerful tool for DUB activity profiling, but their large recognition element impedes cellular permeability and presents an unmet need for small molecule ABPs which can account for regulation of DUB activity in intact cells or organisms. Here, through comprehensive chemoproteomic warhead profiling, we identify cyanopyrrolidine (CNPy) probe IMP-2373 (12) as a small molecule pan-DUB ABP to monitor DUB activity in physiologically relevant live cells. Through proteomics and targeted assays, we demonstrate that IMP-2373 quantitatively engages more than 35 DUBs across a range of non-toxic concentrations in diverse cell lines. We further demonstrate its application to quantification of changes in intracellular DUB activity during pharmacological inhibition and during MYC deregulation in a model of B cell lymphoma. IMP-2373 thus offers a complementary tool to ubiquitin ABPs to monitor dynamic DUB activity in the context of disease-relevant phenotypes.
AU  - Conole,D
AU  - Cao,F
AU  - Am,Ende CW
AU  - Xue,L
AU  - Kantesaria,S
AU  - Kang,D
AU  - Jin,J
AU  - Owen,D
AU  - Lohr,L
AU  - Schenone,M
AU  - Majmudar,JD
AU  - Tate,EW
DO  - 10.1002/anie.202311190
PY  - 2023///
SN  - 1433-7851
TI  - Discovery of a potent deubiquitinase (DUB) small molecule activitybased probe enables broad spectrum DUB activity profiling in living cells
T2  - Angewandte Chemie International Edition
UR  - http://dx.doi.org/10.1002/anie.202311190
UR  - https://www.ncbi.nlm.nih.gov/pubmed/37779326
UR  - https://onlinelibrary.wiley.com/doi/10.1002/anie.202311190
UR  - http://hdl.handle.net/10044/1/106865
VL  - 62
ER  -

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