Potent and selective nonpeptide inhibitors of caspases 3 and 7

5-Dialkylaminosulfonylisatins have been identified as potent, nonpeptide in hibitors of caspases 3 and 7. The most active compound within this series ( 34) inhibited caspases 3 and 7 in the 2-6 nM range and exhibited approximat ely 1000-fold selectivity for caspases 3 and 7 versus a panel of five other caspases (1, 2, 4, 6, and 8) and was at least 20-fold more selective versu s caspase 9. Sequence alignments of the active site residues of the caspase s strongly suggest that the basis of this selectivity is due to binding in the St subsite comprised of residues Tyr204, Trp206, and Phe256 which are u nique to caspases 3 and 7. These compounds inhibit apoptosis in three cell- based models: human Jurkat T cells, human chondrocytes, and mouse bone marr ow neutrophils.