Journal
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 142, Issue 28, Pages 12020-12026Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jacs.0c04527
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Funding
- Cancer Research UK [C29637/A20183]
- Royal Thai Government scholarship
- Swiss National Science Foundation (Early Postdoc Mobility Fellowship) [P2ELP2_175069]
- Francis Crick Institute from Cancer Research UK [FC001097, FC010636]
- UK Medical Research Council [FC001097, FC010636]
- Wellcome Trust [FC001097, FC010636]
- Swiss National Science Foundation (SNF) [P2ELP2_175069] Funding Source: Swiss National Science Foundation (SNF)
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Ubiquitin carboxy-terminal hydrolase L1 (UCHL1) is a deubiquitylating enzyme that is proposed as a potential therapeutic target in neurodegeneration, cancer, and liver and lung fibrosis. Herein we report the discovery of the most potent and selective UCHL1 probe (IMP-1710) to date based on a covalent inhibitor scaffold and apply this probe to identify and quantify target proteins in intact human cells. IMP-1710 stereoselectively labels the catalytic cysteine of UCHL1 at low nanomolar concentration in cells. We further demonstrate that potent and selective UCHL1 inhibitors block pro-fibrotic responses in a cellular model of idiopathic pulmonary fibrosis, supporting the potential of UCHL1 as a potential therapeutic target in fibrotic diseases.
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