1. Identification and validation of selective deubiquitinase inhibitors.
- Author
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Varca AC, Casalena D, Chan WC, Hu B, Magin RS, Roberts RM, Liu X, Zhu H, Seo HS, Dhe-Paganon S, Marto JA, Auld D, and Buhrlage SJ
- Subjects
- 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 antagonists & inhibitors, Enzyme Inhibitors pharmacology, Small Molecule Libraries pharmacology
- Abstract
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.)
- Published
- 2021
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