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
  • 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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