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Discovery of a potent and selective covalent inhibitor and activity-based probe for the deubiquitylating enzyme UCHL1, with anti-fibrotic activity

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Title: Discovery of a potent and selective covalent inhibitor and activity-based probe for the deubiquitylating enzyme UCHL1, with anti-fibrotic activity
Authors: Panyain, N
Godinat, A
Lanyon-Hogg, T
Lachiondo-Ortega, S
Will, EJ
Soudy, C
Mondal, M
Mason, K
Elkhalifa, S
Smith, L
Harrigan, JA
Tate, EW
Item Type: Journal Article
Abstract: Ubiquitin carboxy-terminal hydrolase L1 (UCHL1) is a deubiquitylating enzyme which 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.
Issue Date: 15-Jul-2020
Date of Acceptance: 24-Jun-2020
URI: http://hdl.handle.net/10044/1/80205
DOI: 10.1021/jacs.0c04527
ISSN: 0002-7863
Publisher: American Chemical Society (ACS)
Start Page: 12020
End Page: 12026
Journal / Book Title: Journal of the American Chemical Society
Volume: 142
Issue: 28
Copyright Statement: © 2020 American Chemical Society. This is an open access article published under a Creative Commons Attribution (CC-BY) License, which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
Sponsor/Funder: Cancer Research UK
Funder's Grant Number: C29637/A9913
Keywords: 03 Chemical Sciences
General Chemistry
Publication Status: Published
Article Number: jacs.0c04527
Online Publication Date: 2020-06-24
Appears in Collections:Chemistry
Biological and Biophysical Chemistry
Faculty of Natural Sciences



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