An ‘exquisitely selective’ tool

Mission Therapeutics and Imperial College London report on deubiquitylating enzyme probe

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LONDON & CAMBRIDGE, U.K.—Scientists from the Tate Group at Imperial College London worked closely with drug discovery and development company Mission Therapeutics to develop what they call “the first exquisitely selective probe for a deubiquitylating enzyme (DUB),” reporting in July on their work via a publication in the peer-reviewed Journal of the American Chemical Society (JACS).
In the paper, titled “Discovery of a potent and selective covalent inhibitor and activity-based probe for the deubiquitylating enzyme UCHL1, with anti-fibrotic activity,” Mission and the Tate Group report discovery of IMP-1710, a potent and selective activity-based probe for DUB UCHL1.
Among the points they share is that “outstanding selectivity” was demonstrated against a broad panel of other DUBs and confirmed through proteomic profiling. As the collaborators note, such high-quality, selective chemical probes can be powerful tools in unveiling novel biology and enabling research into new potential therapeutic targets. Plus, with numerous links to disease pathologies, DUBs have attracted increasing interest as possible drug targets.
Over 100 human DUBs—which are responsible for reversibly modifying proteins by removing ubiquitin “labels”—have been identified, expressed in many different cell types, with multiple different functions including regulating degradation of other proteins. For its part, the UCHL1 DUB makes up a little more than one percent of the protein mass of the human brain and is thought to play an important role in diseases—from neurodegeneration to cancer to fibrosis.
The problem as Mission and the Tate Group note, though, is that so far scientists have struggled to understand how UCHL1 works and how it drives disease because there has been no effective inhibitor probe with which to study it.
As a selective UCHL1 probe, IMP-1710 now provides researchers with a 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.
“IMP-1710 represents a great leap forward both for UCHL1 research and for DUB programs more broadly,” said Prof. Edward Tate, professor of chemical biology at Imperial College London and satellite group leader with the Francis Crick Institute. “Mission’s world-leading DUB platform has been fundamental to the success of the project ... This probe promises to unlock a new era of discovery for the important UCHL1 protein.”
In other July news from Mission Therapeutics, the company announced that it has raised $15 million (about £12 million) in equity investment in a round led by existing investor Pfizer Ventures, the venture capital arm of Pfizer Inc. The new capital will support development of Mission’s DUB platform, as well as growth of its pipeline of DUB inhibitor programs.
In addition, Mission and Pfizer Inc. have also expanded their relationship by entering into an evaluation and option agreement for DUB target validation.
Under the terms of the evaluation and option agreement, Pfizer will access specific DUB inhibitors from Mission’s platform and test these compounds in phenotypic screens to validate promising drug targets. Pfizer will then have the option to negotiate target exclusivity for each of the DUBs of interest.
The agreement does not include any of Mission’s own lead DUB programs, such as USP30.

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