Caspase-7 inhibitors

Caspases. Table 2 Caspase inhibitors and their clinical status... 

Apart from these two Vertex compounds, only one other caspase inhibitor, BDN-6556, has been used in clinical trials. This compound belongs to the class of oxamyl dipeptides and was originally developed by Idun Pharmaceuticals (taken over by Pfizer). It is the only pan-caspase inhibitor that has been evaluated in humans. BDN-6556 displays inhibitory activity against all tested human caspases. It is also an irreversible, caspase-specific inhibitor that does not inhibit other major classes of proteases, or other enzymes or receptors. The therapeutic potential of BDN-6556 was first evaluated in several animal models of liver disease because numerous publications suggested that apoptosis contributes substantially to the development of some hepatic diseases, such as alcoholic hepatitis, hepatitis B and C (HBV, HCV), non-alcoholic steato-hepatitis (NASH), and ischemia/reperfusion injury associated with liver transplant. Accordingly, BDN-6556 was tested in a phase I study. The drug was safe and... 

Inhibitors of Natnral Caspase Inhibitors as Anti-Cancer Drngs... 

HBV, hepatitis B HCV, hepatitis C IAP, inhibitor of apoptosis protein DBM, IAP binding motifs INCA, inhibitory CARD NASH, non-alcoholic steatohepatitis PCD, programmed cell death PCI, pan-caspase inhibitor OA, osteoarthritis RA, rheumatoid arthritis Smac, second mitochondria-derived activator of caspases TRAIL, tumor necrosis factor-related apoptosis-inducing ligand. 

Callus BA, Vaux DL (2007) Caspase inhibitors viral, cellular and chemical. Cell Death Differ 14 73-78... 

Linton SD (2005) Caspase inhibitors a pharmaceutical industry perspective. Curr Top Med Chem 5 1697-1717... 

Ma J, Endres M, Moskowitz MA. Synergistic effects of caspase inhibitors and mk-801 in brain injury after transient focal cerebral ischaemia in mice. Br J Pharmacol 1998 124 756-762. 

Ma J, Qiu J, Hirt L, Dalkara T, Moskowitz MA. Synergistic protective effect of caspase inhibitors and bfgf against brain injury induced by transient focal ischaemia. Br J Pharmacol 2001 133 345-350. 

In some studies it has been shown that ITCs can cause increases in the pro-apoptotic caspase enzymes, caspase 3, caspase 8 or caspase However, in other work, specific caspase inhibitors failed to block cell death or cell detachment from the substratum . This suggests that caspase-activation may only be a bystander event, or may only occur after the initiating event of a block in the cell cycle. Indeed, although expression of c-Jun amino-terminal kinase (INK) in response to ITCs has been linked to the pro-apoptotic process, it remains entirely possible that this is a parallel signalling pathway, more closely related to the induction of Phase 1 or Phase 2 enzymes than to the... 

Wang SL, Hawkins CJ, Yoo SJ, Muller HA, Hay BA 1999 The Drosophila caspase inhibitor DIAP1 is essential for cell survival and is negatively regulated by HID. Cell 98 453-463... 

Farber, A., KrtzmiUer, T, MorganeUi, PM, Pfeiffer, J, Groveman, D, Wagner, RJ, Cronenwett, J.L., and PoweU, R.J., 1999, A caspase inhibitor decreases oxidized low-density lipoprotein-induced apoptosis in bovine endothelial cells, J. Surg. Res. 85 323-330. 

Supportive evidence comes from a study showing that intraventricular administration of z-VADfluoromethylketone (fmk), a pan-caspase inhibitor increases the lifespan of SODl transgenic mice by approximately 25% (Li et al, 2000). Furthermore, overexpression of XIAP, a mammalian inhibitor of caspases 3,7 and 9, in spinal motor neurons of mutant SODl mice attenuated disease progression without delaying onset, whilst expression of p35, a baculoviral caspase inhibitor that does not inhibit caspase-9, delayed onset without decreasing disease progression (Inoue et al, 2003). Moreover, caspase-9 was activated in spinal motor neurons of ALS patients. 

Tan pathology Apoptosis Neurotransmission deficits APP production inhibitors A 3-Selective regulators Phosphatase activators GSK-3 inhibitors Cdk5 inhibitors P38 inhibitors JNK inhibitors Caspase inhibitors Neurotrophic agents Phenserine tartrate Posiphen Reticulons Chaperones/SLF-CR Axonyx Axonyx/National Institutes of Health Howard Hughes Medical Institute... 

Caspase inhibitors Antioxidating enzyme enhancers National Cancer Institute (NCI)... 

The EITC-VAD-FMK in situ assay is based on the use of EITC-VAD-EMK in situ marker (Promega Corp., Wisconsin) which is an EITC conjugate of the caspase inhibitor Z-Val-Ala-Asp (OMej-CHaF (Z-VAD-EMK) which irreversibly inhibits caspase-1, -3, -4, and -7. EMK allows delivery of the inhibitor into the cell where it irreversibly binds to activated caspases (E3). The EITC label allows for a direct, one-step assay of caspase activity in living cells or tissue section. The inhibitor... 

Small-molecule inhibitors of caspases would have obvious use as therapeutics. The current medicinal chemistry research literature is rich in studies attempting to achieve this important design goal. In early work, both reversible and irreversible peptide-based inhibitors of various caspases have been developed. Peptidomimetic ketones were also devised for example, acyloxymethyl ketones were designed and developed as potent, time-dependent irreversible caspase inhibitors. 

Investigational agents for the treatment of HCV infection are multiple and include inhibitors of the HCV RNA polymerase such as valopicitabine. Pis such as telaprevir, the ribavirin analogs merimepodib and viramidine, an anti-aminophospholipid antibody, a caspase inhibitor, and the immunomodulator thymosin alpha-1. 

---