Mission and Imperial College London Report Potent and Selective Probe for Deubiquitylating Enzyme UCHL1


Working in close collaboration, scientists from the Tate Group, Imperial College London, and drug discovery and development company, Mission Therapeutics (“Mission”), have discovered the first exquisitely selective probe for a deubiquitylating enzyme (DUB). The research has been published in the leading peer-reviewed Journal of the American Chemical Society (JACS).

In this publication, Mission and the Tate Group report discovery of IMP-1710, a potent and selective activity-based probe for DUB UCHL1. Outstanding selectivity was demonstrated against a broad panel of other DUBs and confirmed through proteomic profiling. Such high quality, selective chemical probes can be powerful tools in unveiling novel biology and enabling research into new potential therapeutic targets.

With numerous links to disease pathologies, DUBs have attracted increasing interest as possible drug targets. DUBs are responsible for reversibly modifying proteins by removing ubiquitin ‘labels’. Over 100 human DUBs have been identified, expressed in many different cell types, with multiple different functions including regulating degradation of other proteins.

The UCHL1 DUB makes up over 1% of the protein mass of the human brain and is thought to play an important role in diseases including neurodegeneration, cancer and fibrosis. To-date, scientists have struggled to understand how UCHL1 works and how it drives disease because there is no effective inhibitor probe with which to study it.

As a selective UCHL1 probe, IMP-1710 provides researchers with the necessary tool to enable substantial progress in the field. In this study, the probe has already been used to inhibit and measure UCHL1 activity inside a range of cells for the first time. In cells from patients with idiopathic pulmonary fibrosis, IMP-1710 was shown to suppress activation of fibrosis pathways.

Commenting on the achievement, Prof. Edward Tate, Professor of Chemical Biology, Imperial College London, and Satellite Group Leader, Francis Crick Institute, said: “IMP-1710 represents a great leap forward both for UCHL1 research and for DUB programmes more broadly. Mission’s world-leading DUB platform has been fundamental to the success of the project. Together, we have reported the first potent and exquisitely selective activity-based probe for any DUB. This probe promises to unlock a new era of discovery for the important UCHL1 protein.”

Dr. Nick Edmunds, Vice President, Head of DUB Discovery at Mission, added: “This publication is the result of a long-term collaboration between Mission and Imperial. It is tremendous to report the research in such a high impact journal. This is a credit to the quality and significance of the science, as well as the dedication of the teams involved. The novel chemical probe will support and drive ongoing research towards treating fibrosis and other diseases with high unmet need.”


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Published on: 07.07.20