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

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

  • J Am Chem Soc. 2020 Jul 15;142(28):12020-12026. doi: 10.1021/jacs.0c04527.
Nattawadee Panyain 1,  Aurélien Godinat 1,  Thomas Lanyon-Hogg 1,  Sofía Lachiondo-Ortega 1,  Edward J Will 1,  Christelle Soudy 2,  Milon Mondal 1,  Katie Mason 3,  Sarah Elkhalifa 3,  Lisa M Smith 3,  Jeanine A Harrigan 3,  Edward W Tate 1 2
Affiliations

Affiliations

  • 1 Department of Chemistry, Molecular Sciences Research Hub, Imperial College London, London, W12 0BZ, U.K.
  • 2 The Francis Crick Institute, London, NW1 1AT, U.K.
  • 3 Mission Therapeutics Ltd, Moneta, Babraham Research Campus, Cambridge, CB22 3AT, U.K.
PMID: 32579346 DOI: 10.1021/jacs.0c04527
Abstract

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.

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