Identification and validation of selective deubiquitinase inhibitors.

Publisher: Cell Press Country of Publication: United States NLM ID: 101676030 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2451-9448 (Electronic) Linking ISSN: 24519448 NLM ISO Abbreviation: Cell Chem Biol Subsets: MEDLINE

Original Publication: Cambridge, MA : Cell Press, 2016-

Deubiquitinating Enzymes/*antagonists & inhibitors ; Enzyme Inhibitors/*pharmacology ; Small Molecule Libraries/*pharmacology; Deubiquitinating Enzymes/metabolism ; Enzyme Inhibitors/chemical synthesis ; Enzyme Inhibitors/chemistry ; Female ; HEK293 Cells ; Humans ; Molecular Structure ; Small Molecule Libraries/chemical synthesis ; Small Molecule Libraries/chemistry

Deubiquitinating enzymes (DUBs) are a class of isopeptidases that regulate ubiquitin dynamics through catalytic cleavage of ubiquitin from protein substrates and ubiquitin precursors. Despite growing interest in DUB biological function and potential as therapeutic targets, few selective small-molecule inhibitors and no approved drugs currently exist. To identify chemical scaffolds targeting specific DUBs and establish a broader framework for future inhibitor development across the gene family, we performed high-throughput screening of a chemically diverse small-molecule library against eight different DUBs, spanning three well-characterized DUB families. Promising hit compounds were validated in a series of counter-screens and orthogonal assays, as well as further assessed for selectivity across expanded panels of DUBs. Through these efforts, we have identified multiple highly selective DUB inhibitors and developed a roadmap for rapidly identifying and validating selective inhibitors of related enzymes.
Competing Interests: Declaration of interests J.A.M. serves on the SAB of 908 Devices and receives sponsored research funding from Vertex and AstraZeneca. S.J.B. serves on the SAB of Adenoid Cystic Carcinoma Foundation. The authors have submitted patent applications related to compounds in this manuscript.
(Copyright © 2021 Elsevier Ltd. All rights reserved.)

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R01 CA233800 United States CA NCI NIH HHS; R21 CA247671 United States CA NCI NIH HHS

Keywords: deubiquitinase; high-throughput screening; small-molecule inhibitor

0 (Enzyme Inhibitors)
0 (Small Molecule Libraries)
EC 3.4.19.12 (Deubiquitinating Enzymes)

Date Created: 20210615 Date Completed: 20220120 Latest Revision: 20221217

20221217

PMC9473745

10.1016/j.chembiol.2021.05.012

34129829