Discovery of a potent and selective covalent inhibitor and activity-based probe for the deubiquitylating enzyme UCHL1, with anti-fibrotic activity. Nattawadee Panyain Aurélien Godinat Thomas Lanyon-Hogg Sofía Lachiondo-Ortega Edward J Will Christelle Soudy Milon Mondal Katie Mason Sarah Elkhalifa Lisa M Smith Jeanine A Harrigan Edward W Tate 10779/crick.12708416.v1 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 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. 2020-07-24 13:42:28 Tate - sat PC General Chemistry 03 Chemical Sciences