Structure Merging Approach Leads to New Dual Potent and Selective USP25/USP28 Inhibitors

  • J Med Chem. 2026 May 14;69(9):10140-10168. doi: 10.1021/acs.jmedchem.5c03045.
Victor Hernandez-Olmos  1  2 ,  Jonathan Vincent Patzke  3 ,  Caroline E Stone  3 ,  Radhika Karal Nair  3 ,  Kathrin Weller  4 ,  Florian Sauer  3 ,  Erik Endres  5 ,  Oumaima Jamai  6 ,  Lea Rachor  6 ,  Cornelia H Warmutz  6 ,  Martin P Schwalm  6  7 ,  Marko Mitrovic  6  7 ,  Vincent Grenier  6  7 ,  Johanna H M Ehrler  6 ,  Anna Proschak  6 ,  Jan Heering  1  2 ,  Christoph Sotriffer  5 ,  Monique P C Mulder  4 ,  Stefan Knapp  6  7 ,  Caroline Kisker  3 ,  Ewgenij Proschak  1  2  6
Affiliations
  • 1. Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany.
  • 2. Fraunhofer Cluster of Excellence Immune-Mediated Diseases CIMD, Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany.
  • 3. Rudolf Virchow Center for Integrative and Translational Bioimaging, Institute for Structural Biology, Julius-Maximilians-University Würzburg, 97080 Würzburg, Germany.
  • 4. Department of Cell and Chemical Biology, Leiden University Medical Centre, Einthovenweg 20, 2300 RC Leiden, The Netherlands.
  • 5. Institute of Pharmacy and Food Chemistry, Julius-Maximilians-University Würzburg, 97074 Würzburg, Germany.
  • 6. Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, 60438 Frankfurt am Main, Germany.
  • 7. Structural Genomics Consortium (SGC), Buchmann Institute for Molecular Life Sciences (BMLS), 60438 Frankfurt am Main, Germany.
PMID: 42017948 DOI: 10.1021/acs.jmedchem.5c03045
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.

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