9suu
USP28 USP domain in complex with T-10531
Structural highlights
FunctionUBP28_HUMAN Deubiquitinase involved in DNA damage response checkpoint and MYC proto-oncogene stability. Involved in DNA damage induced apoptosis by specifically deubiquitinating proteins of the DNA damage pathway such as CLSPN. Also involved in G2 DNA damage checkpoint, by deubiquitinating CLSPN, and preventing its degradation by the anaphase promoting complex/cyclosome (APC/C). In contrast, it does not deubiquitinate PLK1. Specifically deubiquitinates MYC in the nucleoplasm, leading to prevent MYC degradation by the proteasome: acts by specifically interacting with isoform 1 of FBXW7 (FBW7alpha) in the nucleoplasm and counteracting ubiquitination of MYC by the SCF(FBW7) complex. In contrast, it does not interact with isoform 4 of FBXW7 (FBW7gamma) in the nucleolus, allowing MYC degradation and explaining the selective MYC degradation in the nucleolus.[1] [2] [3] [4] Publication Abstract from PubMedUSP25 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. Structure Merging Approach Leads to New Dual Potent and Selective USP25/USP28 Inhibitors.,Hernandez-Olmos V, Patzke JV, Stone CE, Nair RK, Weller K, Sauer F, Endres E, Jamai O, Rachor L, Warmutz CH, Schwalm MP, Mitrovic M, Grenier V, Ehrler JHM, Proschak A, Heering J, Sotriffer C, Mulder MPC, Knapp S, Kisker C, Proschak E J Med Chem. 2026 Apr 22. doi: 10.1021/acs.jmedchem.5c03045. PMID:42017948[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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