Journal Article

PUBDB-2026-01407

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Structure Merging Approach Leads to New Dual Potent and Selective USP25/USP28 Inhibitors

Hernandez-Olmos, V. ; Patzke, J. V. ; Stone, C. E. ; Nair, R. K. ; Weller, K. ; Sauer, F. ; Endres, E. ; Jamai, O. ; Rachor, L. ; Warmutz, C. H. ; Schwalm, M. P. ; Mitrovic, M. ; Grenier, V. ; Ehrler, J. H. M. ; Proschak, A. ; Heering, J. ; Sotriffer, C. ; Mulder, M. P. C. ; Knapp, S. ; Kisker, C. ; Proschak, E. (Corresponding author)

2026
ACS Washington, DC

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Please use a persistent id in citations: doi:10.1021/acs.jmedchem.5c03045  doi:10.3204/PUBDB-2026-01407

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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Contributing Institute(s):

1. EMBL-User (EMBL-User)

Research Program(s):

1. 6G3 - PETRA III (DESY) (POF4-6G3) (POF4-6G3)
2. DFG project G:(GEPRIS)545932924 - E3 Ligasen als neue Zielstrukturen in AML (B02) (545932924) (545932924)
3. DFG project G:(GEPRIS)545933307 - Entwicklung potenter und selektiver USP25- und USP28-Inhibitoren (B06) (545933307) (545933307)
4. GRK 2243 - GRK 2243: Ubiquitylierung verstehen: Von molekularen Mechanismen zu Krankheiten (285767414) (285767414)

Experiment(s):

1. PETRA Beamline P13 (PETRA III)

Appears in the scientific report 2026

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Chemical Reactions ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 5 ; Index Chemicus ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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