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Carbonates are a new class of deubiquitinating enzyme inhibitors (952.5)
Author(s) -
Long Marcus,
Lawson Ann,
Rozhansky Lior,
Hedstrom Lizbeth
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.952.5
Subject(s) - deubiquitinating enzyme , ubiquitin , chemistry , enzyme , cysteine protease , k562 cells , downregulation and upregulation , biochemistry , protease , cell , gene
Deubiquitinating enzymes (DUBs) have emerged as promising drug targets, but few small molecule DUB inhibitors have been identified. Herein we introduce carbonates as a novel class of mechanism‐based DUB inhibitors. Activity profiling was used to determine inhibitor potency and specificity in cell lysates. The most potent inhibitor, C17, has a preference for USP9x and USP7. In K562 cells, C17 (50 micromolar) causes the degradation of Bcr‐Abl kinase, as expected when USP9x is inhibited. In MCF7 cells, C17 (25 micromolar) causes the degradation of Mdm2 and upregulation of P53, as expected when USP7 is inhibited. We believe that carbonates will be useful tools for studying the ubiquitination pathways and provide a new strategy for the design of cysteine protease inhibitors. Grant Funding Source : Supported by the NIH R01 GM100921(LH), HHMI International Student Fellowship (MJCL).