Therapeutics
References 1 LaCasse, EC, Mahoney, DJ, Cheung, HH, Plenchette, S, Baird, S, Korneluk, RG. IAP- targeted therapies for cancer. Oncogene. 2008 Oct 20;27(48):6252-75. 2 Feoktistova, M, Geserick, P, Kellert, B, Dimitrova, DP, Langlais, C, Hupe, M, Cain, K, Macfarlane, M, Häcker, G, Leverkus, M. cIAPs Block Ripoptosome Formation, a RIP1/Caspase-8 Containing Intracellular Cell Death Complex Differentially Regulated by cFLIP Isoforms. Mol Cell. 2011 Aug 5;43(3):449-63. Epub 2011 Jul 7. 3Tenev, T, Bianchi, K, Darding, M, Broemer, M, Langlais, C, Wallberg, F, Zachariou, A, Lopez, J, MacFarlane, M, Cain, K, Meier, P. The Ripoptosome, a signaling platform that assembles in response to genotoxic stress and loss of IAPs. Mol Cell, 2011 Aug 5 (3);43:432-458. 4 Ghavami, S, Hashemi, M, Ande, SR, Yeganeh, B, Xiao, W, Eshraghi, M, Bus, CJ, Kadkhoda, K, Wiechec, E, Halayko, AJ, Los, M. Apoptosis and cancer: mutations within caspase genes. J Med Genet. 2009 Aug;46(8):497-510. Epub 2009 Jun 7. 5 Parsons, MJ, Green, DR. Mitochondria in cell death. Essays Biochem. 2010. 6 Mannhold, R, Fulda, S, Carosati, E. IAP antagonists: promising candidates for cancer therapy. Drug Discov Today. 2010 Mar;15(5-6):210-9. Epub 2010 Jan 21. 7 Nathan, C, Ding, A. Nonresolving inflammation. Cell. 2010 Mar 19;140(6): 871-82. 8 Karin, M, Greten, FR. NF-B: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol. 2005 Oct;5(10):749-59. 9 Gyrd-Hansen, M, Meier, P. IAPs: from caspase inhibitors to modulators of NF-B, inflammation and cancer. Nat Rev Cancer. 2010 Aug;10(8):561-74.
Continued on page 39 38
Smac mimetics: exert anti-tumour activity through four different mechanistic activities
Currently, seven human IAPs have been identified: XIAP, cIAP1, cIAP2, ILP2, BRUCE/Apollon, sur- vivin and livin (ML-IAP)1. IAPs represent the last line of defence against inadvertent cell death sig- nalling by inhibiting caspases and by regulating the pro-survival and apoptosis signalling via death receptor complexes.
Caspases are cysteine-dependent aspartyl-specif- ic proteases and central players in cellular apopto- sis. They are tightly regulated on several levels. Caspases are expressed as inactive zymogens (pro- caspases) and their activation follows a strictly controlled pattern. Caspases can be activated by two distinct pathways: the extrinsic apoptotic pathway triggered by external death ligands and the intrinsic apoptotic pathway that is initiated through effects on the mitochondria. The extrinsic apoptotic pathway is activated when members of the family of TNF-like death lig- ands, including TNF, FasL or Apo2L/TRAIL (Apo2L/tumour-necrosis-factor-related apoptosis- inducing ligand), bind to their respective receptors TNFR1, TNFR2, Fas, DR4 or DR5, ‘death recep- tors’ located on the cell membrane. When cIAP1 and cIAP2 are absent in the death receptor com- plex, the binding of death ligands to their receptors leads to the formation of the death-inducing sig-
nalling complex (DISC) in which adaptor proteins (FADD and/or TRADD) bind with their death domain and induce the recruitment and activation of the initiator caspases, caspase-8 or -10. More recently it has been shown that loss of cIAP1 and cIAP2 alone can lead to caspase-8 activation in the presence of Smac mimetic through the formation of the ripoptosome composed of RIPK1, FADD, caspase-8 or -10 and cFLIP2,3. The activation of caspase-8 or -10 leads to cleavage and activation of the downstream executioner caspases, caspase-3 and -7. These executioner caspases usually remain in an inactive state in the cytosol of the cells. The activation of the executioner caspases eventually results in apoptosis when not inhibited by XIAP2. Caspase-8 can also cleave the pro-apoptotic BH3- only protein Bid to truncated Bid (tBID) which can translocate into the mitochondria triggering the activation of the intrinsic pathway resulting in cytochrome c release and apoptosome formation leading to caspase-9 and -3 activation4. The intrinsic pathway is activated by ‘intrinsic’ cell death signals such as hypoxia, genotoxic stress or other types of cellular stress. These signals lead to mitochondrial outer membrane permeabilisa- tion (MOMP) and the release of several proteins into the cytosol including cytochrome-c,
Drug Discovery World Fall 2011
Page 1 |
Page 2 |
Page 3 |
Page 4 |
Page 5 |
Page 6 |
Page 7 |
Page 8 |
Page 9 |
Page 10 |
Page 11 |
Page 12 |
Page 13 |
Page 14 |
Page 15 |
Page 16 |
Page 17 |
Page 18 |
Page 19 |
Page 20 |
Page 21 |
Page 22 |
Page 23 |
Page 24 |
Page 25 |
Page 26 |
Page 27 |
Page 28 |
Page 29 |
Page 30 |
Page 31 |
Page 32 |
Page 33 |
Page 34 |
Page 35 |
Page 36 |
Page 37 |
Page 38 |
Page 39 |
Page 40 |
Page 41 |
Page 42 |
Page 43 |
Page 44 |
Page 45 |
Page 46 |
Page 47 |
Page 48 |
Page 49 |
Page 50 |
Page 51 |
Page 52 |
Page 53 |
Page 54 |
Page 55 |
Page 56 |
Page 57 |
Page 58 |
Page 59 |
Page 60 |
Page 61 |
Page 62 |
Page 63 |
Page 64 |
Page 65 |
Page 66 |
Page 67 |
Page 68 |
Page 69 |
Page 70 |
Page 71 |
Page 72 |
Page 73 |
Page 74 |
Page 75 |
Page 76 |
Page 77 |
Page 78 |
Page 79 |
Page 80 |
Page 81 |
Page 82 |
Page 83 |
Page 84 |
Page 85 |
Page 86 |
Page 87 |
Page 88 |
Page 89 |
Page 90 |
Page 91 |
Page 92