title: Strategies for the identification of novel inhibitors of deubiquitinating enzymes.
abstract: Dysregulation of the UPS (ubiquitin-proteasome system) has been implicated in a wide range of pathologies including cancer, neurodegeneration and viral infection. Inhibiting the proteasome has been shown to be an effective therapeutic strategy in humans; yet toxicity with this target remains high. DUBs (deubiquitinating enzymes) represent an alternative target in the UPS with low predicted toxicity. Currently, there are no DUB inhibitors that have been used clinically. To address this situation, Progenra has developed a novel assay to measure the proteolytic cleavage of Ub (ubiquitin) or UBL (Ub-like protein) conjugates such as SUMO (small Ub-related modifier), NEDD8 (neural-precursor-cell-expressed, developmentally down-regulated 8) or ISG15 (interferon-stimulated gene 15) by isopeptidases. In this review, current platforms for detecting DUB inhibitors are discussed and the advantages and disadvantages of the approaches are underlined.
authors.affiliation: Progenra Inc., 271A Great Valley Parkway, Malvern, PA 19355, USA. Goldenberg@progenra.com
authors.forename: Seth J
authors.initials: SJ
authors.lastname: Goldenberg
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: McDermott
authors.forename: Tauseef R
authors.initials: TR
authors.lastname: Butt
authors.forename: Michael R
authors.initials: MR
authors.lastname: Mattern
authors.forename: Benjamin
authors.initials: B
authors.lastname: Nicholson
mesh_terms: D001681:Biological Assay / Q000379:methods*; D004194:Disease; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000378:metabolism* / Q000627:therapeutic use; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D054467:Phospholipases A2 / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D007527:Isoenzymes; D025801:Ubiquitin; D054467:Phospholipases A2; D010450:Endopeptidases; D046988:Proteasome Endopeptidase Complex
references.citation: Cancer Res. 2004 Mar 15;64(6):1920-3
references.pmid: 15026324
references.citation: Methods Enzymol. 2005;399:634-53
references.pmid: 16338386
references.citation: J Biol Chem. 2005 Sep 9;280(36):32026-34
references.pmid: 16040601
references.citation: Semin Cell Dev Biol. 2004 Apr;15(2):211-20
references.pmid: 15209381
references.citation: Mol Cell. 2004 Mar 26;13(6):879-86
references.pmid: 15053880
references.citation: J Biol Chem. 1994 Oct 14;269(41):25381-6
references.pmid: 7929235
references.citation: Mol Cancer Ther. 2005 Apr;4(4):686-92
references.pmid: 15827343
references.citation: Cell. 2005 Dec 2;123(5):773-86
references.pmid: 16325574
references.citation: PLoS Biol. 2006 Feb;4(2):e27
references.pmid: 16402859
references.citation: Mol Cell. 2005 Feb 4;17(3):331-9
references.pmid: 15694335
references.citation: Cancer. 2006 Aug 15;107(4):668-75
references.pmid: 16826582
references.citation: J Virol. 2007 Jun;81(11):6007-18
references.pmid: 17392370
references.citation: Proc Natl Acad Sci U S A. 2007 Feb 27;104(9):3502-7
references.pmid: 17360673
references.citation: Nature. 2003 Aug 14;424(6950):797-801
references.pmid: 12917690
references.citation: Cancer Cell. 2005 Nov;8(5):407-19
references.pmid: 16286248
references.citation: PLoS One. 2007 Apr 18;2(4):e381
references.pmid: 17440617
references.citation: Biochemistry. 1998 Mar 10;37(10):3358-68
references.pmid: 9521656
references.citation: Genes Dev. 1997 Aug 1;11(15):1974-86
references.pmid: 9271120
references.citation: Mol Cell Biol. 2007 Jul;27(13):5029-39
references.pmid: 17452457
references.citation: Cancer Cell. 2004 Mar;5(3):253-61
references.pmid: 15050917
references.citation: J Virol. 2006 Jun;80(12):6003-12
references.pmid: 16731939
references.citation: J Biol Chem. 2007 Mar 30;282(13):9805-9812
references.pmid: 17261583
references.citation: Nature. 2003 Aug 14;424(6950):793-6
references.pmid: 12917689
references.citation: Biol Proced Online. 1998 Jul 20;1:92-99
references.pmid: 12734599
references.citation: Ann Nutr Aliment. 1979;33(1):57-89
references.pmid: 382958
references.citation: Nature. 1981 Feb 12;289(5798):604-6
references.pmid: 7464926
references.citation: Biochemistry. 1998 Feb 17;37(7):1868-79
references.pmid: 9485312
references.citation: Br J Dermatol. 2006 Jul;155(1):182-5
references.pmid: 16792771
references.citation: Oncogene. 2004 Mar 15;23(11):2028-36
references.pmid: 15021890
references.citation: Biochim Biophys Acta. 2004 Nov 29;1695(1-3):189-207
references.pmid: 15571815
references.citation: Future Oncol. 2007 Apr;3(2):191-9
references.pmid: 17381419
references.citation: Anal Biochem. 2005 Aug 15;343(2):244-55
references.pmid: 15963938
references.citation: Cell Cycle. 2004 Jun;3(6):689-92
references.pmid: 15118411
references.citation: Blood. 2001 Aug 1;98(3):636-42
references.pmid: 11468161
references.citation: Cell. 1984 May;37(1):43-55
references.pmid: 6327059
references.citation: J Neurochem. 2005 Nov;95(3):724-31
references.pmid: 16190881
references.citation: Biochem Biophys Res Commun. 2002 Jun 14;294(3):700-9
references.pmid: 12056827
references.citation: Oncogene. 1998 Nov 12;17(19):2543-7
references.pmid: 9824166
references.citation: Anal Biochem. 2007 Jan 1;360(1):138-43
references.pmid: 17118327
references.citation: Mol Biol Cell. 2006 Dec;17(12):5324-36
references.pmid: 17035631
references.citation: Biochim Biophys Acta. 2004 Nov 29;1695(1-3):45-54
references.pmid: 15571808
references.citation: Mol Cell. 2005 Aug 19;19(4):547-57
references.pmid: 16109378
references.citation: Nature. 2002 Apr 11;416(6881):648-53
references.pmid: 11923872
references.citation: Trends Cell Biol. 2006 Jul;16(7):362-9
references.pmid: 16762551
references.citation: Chem Biol. 2003 Sep;10(9):837-46
references.pmid: 14522054
references.citation: Annu Rev Biochem. 1998;67:425-79
references.pmid: 9759494
references.citation: Ann Neurol. 2002 Jan;51(1):133-6
references.pmid: 11782995
references.citation: Biochim Biophys Acta. 2007 Jun;1773(6):694-706
references.pmid: 17475350
references.citation: J Biol Chem. 2000 Mar 24;275(12):8945-51
references.pmid: 10722742