Structure Merging Approach Leads to New Dual Potent and Selective USP25/USP28 Inhibitors
Year: 2026
Type: article
Abstract: USP25 and USP28 are critical deubiquitylases (DUBs) that have been implicated in various diseases, particularly cancer and cardiac dysfunction. Several small-molecule inhibitors have been reported, exhibiting dual inhibitory activity in the low micromolar range. In this study, we present a strategy that merges structural features of the previously identified inhibitors AZ1 and vismodegib to develop a new class of potent dual inhibitors. Several of these newly synthesized compounds exhibit high potency across multiple orthogonal assays and demonstrate excellent selectivity over other ubiquitin-specific proteases. Moreover, a suitable negative control has also been identified, supporting the validity of the observed effects in cellular assays. These results highlight the potential of these compounds to serve as advanced chemical probes for dual USP25/USP28 inhibition and as candidates for further therapeutic development.
Source: Journal of Medicinal Chemistry
Authors: Victor Hernandez-Olmos, Jonathan Vincent Patzke, Caroline E. Stone, Radhika Karal Nair, Kathrin Weller, Florian Sauer, Erik Endres, Oumaima Jamai, Lea Rachor, Cornelia H. Warmutz, Martin P. Schwalm, Marko Mitrovic, Vincent Grenier, Johanna H. M. Ehrler, Anna Proschak, Jan Heering, Christoph Sotriffer, Monique P. C. Mulder, Stefan Knapp, Caroline Kisker, Ewgenij Proschak
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,500
Funders: McGill University, Diamond Light Source, European Federation of Pharmaceutical Industries and Associations, Deutsche Forschungsgemeinschaft, Universiteit Leiden, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Kungliga Tekniska Högskolan, Innovative Medicines Initiative, Horizon 2020 Framework Programme
OpenAlex ID: W7155171926