Strategies for the identification of novel inhibitors of deubiquitinating enzymes.
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.
Goldenberg
Seth J
SJ
Progenra Inc., 271A Great Valley Parkway, Malvern, PA 19355, USA. Goldenberg@progenra.com
McDermott
Jeffrey L
JL
Butt
Tauseef R
TR
Mattern
Michael R
MR
Nicholson
Benjamin
B
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*
D004791:Enzyme Inhibitors; D007527:Isoenzymes; D025801:Ubiquitin; D054467:Phospholipases A2; D010450:Endopeptidases; D046988:Proteasome Endopeptidase Complex
Cancer Res. 2004 Mar 15;64(6):1920-3
15026324
Methods Enzymol. 2005;399:634-53
16338386
J Biol Chem. 2005 Sep 9;280(36):32026-34
16040601
Semin Cell Dev Biol. 2004 Apr;15(2):211-20
15209381
Mol Cell. 2004 Mar 26;13(6):879-86
15053880
J Biol Chem. 1994 Oct 14;269(41):25381-6
7929235
Mol Cancer Ther. 2005 Apr;4(4):686-92
15827343
Cell. 2005 Dec 2;123(5):773-86
16325574
PLoS Biol. 2006 Feb;4(2):e27
16402859
Mol Cell. 2005 Feb 4;17(3):331-9
15694335
Cancer. 2006 Aug 15;107(4):668-75
16826582
J Virol. 2007 Jun;81(11):6007-18
17392370
Proc Natl Acad Sci U S A. 2007 Feb 27;104(9):3502-7
17360673
Nature. 2003 Aug 14;424(6950):797-801
12917690
Cancer Cell. 2005 Nov;8(5):407-19
16286248
PLoS One. 2007 Apr 18;2(4):e381
17440617
Biochemistry. 1998 Mar 10;37(10):3358-68
9521656
Genes Dev. 1997 Aug 1;11(15):1974-86
9271120
Mol Cell Biol. 2007 Jul;27(13):5029-39
17452457
Cancer Cell. 2004 Mar;5(3):253-61
15050917
J Virol. 2006 Jun;80(12):6003-12
16731939
J Biol Chem. 2007 Mar 30;282(13):9805-9812
17261583
Nature. 2003 Aug 14;424(6950):793-6
12917689
Biol Proced Online. 1998 Jul 20;1:92-99
12734599
Ann Nutr Aliment. 1979;33(1):57-89
382958
Nature. 1981 Feb 12;289(5798):604-6
7464926
Biochemistry. 1998 Feb 17;37(7):1868-79
9485312
Br J Dermatol. 2006 Jul;155(1):182-5
16792771
Oncogene. 2004 Mar 15;23(11):2028-36
15021890
Biochim Biophys Acta. 2004 Nov 29;1695(1-3):189-207
15571815
Future Oncol. 2007 Apr;3(2):191-9
17381419
Anal Biochem. 2005 Aug 15;343(2):244-55
15963938
Cell Cycle. 2004 Jun;3(6):689-92
15118411
Blood. 2001 Aug 1;98(3):636-42
11468161
Cell. 1984 May;37(1):43-55
6327059
J Neurochem. 2005 Nov;95(3):724-31
16190881
Biochem Biophys Res Commun. 2002 Jun 14;294(3):700-9
12056827
Oncogene. 1998 Nov 12;17(19):2543-7
9824166
Anal Biochem. 2007 Jan 1;360(1):138-43
17118327
Mol Biol Cell. 2006 Dec;17(12):5324-36
17035631
Biochim Biophys Acta. 2004 Nov 29;1695(1-3):45-54
15571808
Mol Cell. 2005 Aug 19;19(4):547-57
16109378
Nature. 2002 Apr 11;416(6881):648-53
11923872
Trends Cell Biol. 2006 Jul;16(7):362-9
16762551
Chem Biol. 2003 Sep;10(9):837-46
14522054
Annu Rev Biochem. 1998;67:425-79
9759494
Ann Neurol. 2002 Jan;51(1):133-6
11782995
Biochim Biophys Acta. 2007 Jun;1773(6):694-706
17475350
J Biol Chem. 2000 Mar 24;275(12):8945-51
10722742