Discovery of a potent and selective covalent inhibitor and activity-based probe for the deubiquitylating enzyme UCHL1, with anti-fibrotic activity.
journal contributionposted on 24.07.2020, 13:42 authored by 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
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.