%0 Journal Article %A Panyain, Nattawadee %A Godinat, Aurélien %A Lanyon-Hogg, Thomas %A Lachiondo-Ortega, Sofía %A Will, Edward J %A Soudy, Christelle %A Mondal, Milon %A Mason, Katie %A Elkhalifa, Sarah %A Smith, Lisa M %A Harrigan, Jeanine A %A Tate, Edward W %D 2020 %T Discovery of a potent and selective covalent inhibitor and activity-based probe for the deubiquitylating enzyme UCHL1, with anti-fibrotic activity. %U https://crick.figshare.com/articles/journal_contribution/Discovery_of_a_potent_and_selective_covalent_inhibitor_and_activity-based_probe_for_the_deubiquitylating_enzyme_UCHL1_with_anti-fibrotic_activity_/12708416 %2 https://crick.figshare.com/ndownloader/files/24062900 %K Tate - sat %K PC %K General Chemistry %K 03 Chemical Sciences %X Ubiquitin carboxy-terminal hydrolase L1 (UCHL1) is a deubiquitylating enzyme which 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. %I The Francis Crick Institute