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. Epub 2020 Jul 1.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Drug Discovery*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • HeLa Cells
  • Humans
  • Molecular Structure
  • Ubiquitin Thiolesterase / antagonists & inhibitors*
  • Ubiquitin Thiolesterase / metabolism

Substances

  • Enzyme Inhibitors
  • UCHL1 protein, human
  • Ubiquitin Thiolesterase