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Discovery of a potent and selective covalent inhibitor and activity-based probe for the deubiquitylating enzyme UCHL1 displays antifibrotic activity

Congratulations to former PhD student Dr Nattawadee Panyain on her , in close collaboration with . Congratulations also to former and current group members Dr Aurélien Godinat, Dr Thomas Lanyon-Hogg, Sofía Lachiondo-Ortega, Edward Will, Christelle Soudy, and Dr Milon Mondal for their contributions to this project.

Ubiquitin carboxy-terminal hydrolase L1 (UCHL1) is a deubiquitylating enzyme that has been proposed as a potential therapeutic target with implications in neurodegeneration, cancer, and liver and lung fibrosis. This research details the discovery of a potent and highly selective inhibitor (IMP-1710) against UCHL1 to date. IMP-1710 was then further profiled and found to suppress activation of fibrosis pathways, thereby demonstrating its antifibrotic activity.

A by Mission Therapeutics features comments from group leader Prof. Ed Tate and Dr Nick Edmunds (Vice President, Head of DUB discovery at Mission Therapeutics) on this achievement.

We would like to thank CRUK for supporting this project.

Well done to everyone involved!