Identification and Evaluation of Small Molecule Pan-Caspase Inhibitors in Huntington's Disease Models

Arrasate, 2004, Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death, Nature, 431, 805, 10.1038/nature02998 Baskin-Bey, 2007, Clinical trial of the pan-caspase inhibitor, IDN-6556, in human liver preservation injury, Am. J. Transplant., 7, 218, 10.1111/j.1600-6143.2006.01595.x Bieth, 1995, Theoretical and practical aspects of proteinase inhibition kinetics, Methods Enzymol., 248, 59, 10.1016/0076-6879(95)48007-2 Brak, 2008, Identification of a new class of nonpeptidic inhibitors of cruzain, J. Am. Chem. Soc., 130, 6404, 10.1021/ja710254m Brik, 2005, 1,2,3-triazole as a peptide surrogate in the rapid synthesis of HIV-1 protease inhibitors, ChemBioChem, 6, 1167, 10.1002/cbic.200500101 Charvin, 2008, Haloperidol protects striatal neurons from dysfunction induced by mutated huntingtin in vivo, Neurobiol. Dis., 29, 22, 10.1016/j.nbd.2007.07.028 Chen, 2000, Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease, Nat. Med., 6, 797, 10.1038/77528 Cornelis, 2007, Inflammatory caspases: targets for novel therapies, Curr. Pharm. Des., 13, 367, 10.2174/138161207780163006 Davies, 1997, Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation, Cell, 90, 537, 10.1016/S0092-8674(00)80513-9 DiFiglia, 1997, Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain, Science, 277, 1990, 10.1126/science.277.5334.1990 Dunah, 2002, Sp1 and TAFII 130 transcriptional activity disrupted in early Huntington's disease, Science, 296, 2238, 10.1126/science.1072613 Ekici, 2006, Design, synthesis, and evaluation of aza-peptide Michael acceptors as selective and potent inhibitors of caspases-2, -3, -6, -7, -8, -9, and -10, J. Med. Chem., 49, 5728, 10.1021/jm0601405 Fan, 2007, Altered NMDA receptor trafficking in a yeast artificial chromosome transgenic mouse model of Huntington's disease, J. Neurosci., 27, 3768, 10.1523/JNEUROSCI.4356-06.2007 Gafni, 2002, Calpain activation in Huntington's disease, J. Neurosci., 22, 4842, 10.1523/JNEUROSCI.22-12-04842.2002 Gafni, 2004, Inhibition of calpain cleavage of huntingtin reduces toxicity: accumulation of calpain/caspase fragments in the nucleus, J. Biol. Chem., 279, 20211, 10.1074/jbc.M401267200 Gervais, 1998, Caspases cleave focal adhesion kinase during apoptosis to generate a FRNK-like polypeptide, J. Biol. Chem., 273, 17102, 10.1074/jbc.273.27.17102 Gervais, 1999, Involvement of caspases in proteolytic cleavage of Alzheimer's amyloid-beta precursor protein and amyloidogenic A beta peptide formation, Cell, 97, 395, 10.1016/S0092-8674(00)80748-5 Goldberg, 1996, Cleavage of huntingtin by apopain, a proapoptotic cysteine protease, is modulated by the polyglutamine tract, Nat. Genet., 13, 442, 10.1038/ng0896-442 Graham, 2006, Cleavage at the caspase-6 site is required for neuronal dysfunction and degeneration due to mutant huntingtin, Cell, 125, 1179, 10.1016/j.cell.2006.04.026 Gutekunst, 1999, Nuclear and neuropil aggregates in Huntington's disease: relationship to neuropathology, J. Neurosci., 19, 2522, 10.1523/JNEUROSCI.19-07-02522.1999 1993, A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes, Cell, 72, 971, 10.1016/0092-8674(93)90585-E Hermel, 2004, Specific caspase interactions and amplification are involved in selective neuronal vulnerability in Huntington's disease, Cell Death Differ., 11, 424, 10.1038/sj.cdd.4401358 Inagaki, 2007, Characterization and optimization of selective, nonpeptidic inhibitors of cathepsin S with an unprecedented binding mode, J. Med. Chem., 50, 2693, 10.1021/jm070111+ Kaltenbach, 2010, Composite primary neuronal high-content screening assay for Huntington's disease incorporating non-cell-autonomous interactions, Biomol. Screen, 15, 806, 10.1177/1087057110373392 Li, 2002, Interaction of Huntington disease protein with transcriptional activator Sp1, Mol. Cell. Biol., 22, 1277, 10.1128/MCB.22.5.1277-1287.2002 Linton, 2004, Oxamyl dipeptide caspase inhibitors developed for the treatment of stroke, Bioorg. Med. Chem. Lett., 14, 2685, 10.1016/j.bmcl.2003.12.106 Linton, 2005, First-in-class pan caspase inhibitor developed for the treatment of liver disease, J. Med. Chem., 48, 6779, 10.1021/jm050307e Lunkes, 2002, Proteases acting on mutant huntingtin generate cleaved products that differentially build up cytoplasmic and nuclear inclusions, Mol. Cell, 10, 259, 10.1016/S1097-2765(02)00602-0 Martindale, 1998, Length of huntingtin and its polyglutamine tract influences localization and frequency of intracellular aggregates, Nat. Genet., 18, 150, 10.1038/ng0298-150 O'Brien, 2004, Prospects for caspase inhibitors, Mini Rev. Med. Chem., 4, 153, 10.2174/1389557043487448 Patterson, 2006, Identification of selective, nonpeptidic nitrile inhibitors of cathepsin S using the substrate activity screening method, J. Med. Chem., 49, 6298, 10.1021/jm060701s Pop, 2009, Human caspases: activation, specificity, and regulation, J. Biol. Chem., 284, 21777, 10.1074/jbc.R800084200 Reed, 2002, Apoptosis-based therapies, Nat. Rev. Drug Discov., 1, 111, 10.1038/nrd726 Rozman-Pungercar, 2003, Inhibition of papain-like cysteine proteases and legumain by caspase-specific inhibitors: when reaction mechanism is more important than specificity, Cell Death Differ., 10, 881, 10.1038/sj.cdd.4401247 Sawada, 2007, Characterization of neuron-specific huntingtin aggregates in human huntingtin knock-in mice, Neurosci. Res., 57, 559, 10.1016/j.neures.2007.01.002 Schulz, 1998, Extended therapeutic window for caspase inhibition and synergy with MK-801 in the treatment of cerebral histotoxic hypoxia, Cell Death Differ., 5, 847, 10.1038/sj.cdd.4400420 Schweizer, 2003, Crystal structure of xaspase-2, apical initiator of the intrinsic apoptotic pathway, J. Biol. Chem., 278, 42441, 10.1074/jbc.M304895200 Sexton, 2007, Design of cell-permeable, fluorescent activity-based probes for the lysosomal cysteine protease asparaginyl endopeptidase (AEP)/legumain, Bioorg. Med. Chem. Lett., 17, 649, 10.1016/j.bmcl.2006.10.100 Stack, 2007, Neuroprotective effects of synaptic modulation in Huntington's disease R6/2 mice, J. Neurosci., 27, 12908, 10.1523/JNEUROSCI.4318-07.2007 Stennicke, 1999, Caspases: preparation and characterization, Methods, 17, 313, 10.1006/meth.1999.0745 Talanian, 1997, Substrate specificities of caspase family proteases, J. Biol. Chem., 272, 9677, 10.1074/jbc.272.15.9677 Thornberry, 1997, A combinatorial approach defines specificities of members of the caspase family and granzyme B. Functional relationships established for key mediators of apoptosis, J. Biol. Chem., 272, 17907, 10.1074/jbc.272.29.17907 Toulmond, 2004, Neuroprotective effects of M826, a reversible caspase-3 inhibitor, in the rat malonate model of Huntington's disease, Br. J. Pharmacol., 141, 689, 10.1038/sj.bjp.0705662 Trettel, 2000, Dominant phenotypes produced by the HD mutation in STHdh(Q111) striatal cells, Hum. Mol. Genet., 9, 2799, 10.1093/hmg/9.19.2799 Wellington, 1998, Caspase cleavage of gene products associated with triplet expansion disorders generates truncated fragments containing the polyglutamine tract, J. Biol. Chem., 273, 9158, 10.1074/jbc.273.15.9158 Wellington, 2000, Inhibiting caspase cleavage of huntingtin reduces toxicity and aggregate formation in neuronal and nonneuronal cells, J. Biol. Chem., 275, 19831, 10.1074/jbc.M001475200 Wellington, 2002, Caspase cleavage of mutant huntingtin precedes neurodegeneration in Huntington's disease, J. Neurosci., 22, 7862, 10.1523/JNEUROSCI.22-18-07862.2002 Wood, 2005, Substrate activity screening: a fragment-based method for the rapid identification of nonpeptidic protease inhibitors, J. Am. Chem. Soc., 127, 15521, 10.1021/ja0547230 Zhai, 2005, In vitro analysis of Huntingtin-mediated transcriptional repression reveals multiple transcription factor targets, Cell, 123, 1241, 10.1016/j.cell.2005.10.030