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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

preprint
submitted on 29.10.2019 and posted on 31.10.2019 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.

Funding

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)

History

Email Address of Submitting Author

e.tate@imperial.ac.uk

Institution

Imperial College London

Country

United Kingdom

ORCID For Submitting Author

0000-0003-2213-5814

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

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