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