Discovery of a Potent and Selective Covalent Inhibitor and Activity-Based Probe for the Deubiquitylating Enzyme UCHL1, with Antifibrotic Activity.
Nattawadee PanyainAurélien GodinatThomas Lanyon-HoggSofía Lachiondo-OrtegaEdward J WillChristelle SoudyMilon MondalKatie MasonSarah ElkhalifaLisa M SmithJeanine A HarriganEdward William TatePublished in: Journal of the American Chemical Society (2020)
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.
Keyphrases
- idiopathic pulmonary fibrosis
- living cells
- small molecule
- anti inflammatory
- quantum dots
- human health
- induced apoptosis
- high throughput
- papillary thyroid
- risk assessment
- cell cycle arrest
- squamous cell carcinoma
- cell death
- signaling pathway
- cell proliferation
- single cell
- young adults
- endoplasmic reticulum stress
- single molecule
- crystal structure
- pulmonary fibrosis