Discovery of a Potent and Selective Covalent Inhibitor and Activity-Based Probe for the Deubiquitylating Enzyme UCHL1, with Antifibrotic Activity

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.