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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

submitted on 29.10.2019, 11:52 and posted on 31.10.2019, 17:10 by Nattawadee Panyain, Aurélien Godinat, Thomas Lanyon-Hogg, Sofía Lachiondo-Ortega, Edward J. Will, Christelle Soudy, Katie Mason, Sarah Elkhalifa, Lisa M. Smith, Jeanine A. Harrigan, Edward Tate
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, and we show that a previously claimed UCHL1 inhibitor (LDN-57444) fails to engage UCHL1 in cells. We further demonstrate that potent UCHL1 inhibitors block pro-fibrotic responses in a cellular model of idiopathic pulmonary fibrosis, supporting a potential therapeutic role for UCHL1 inhibition and providing a basis for future therapeutic development of selective UCHL1 inhibitors.


Cancer Research UK (Programme Foundation Award C29637/A20183)

Royal Thai Government scholarship (PhD studentship)

Swiss National Science Foundation (Early Postdoc Mobility Fellowship, P2ELP2_175069)

Cancer Research UK (FC001097, FC010636)

UK Medical Research Council (FC001097, FC010636)

Wellcome Trust (FC001097, FC010636)


Email Address of Submitting Author


Imperial College London


United Kingdom

ORCID For Submitting Author


Declaration of Conflict of Interest

K.M., S.E., L.M.S., and J.A.H. are employees of Mission Therapeutics Ltd; E.W.T. is a Director and shareholder in Myricx Pharma Ltd.

Version Notes

Version number 1