Potent and selective nonpeptide inhibitors of caspases 3 and 7.

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Lee D, Long SA, Murray JH, Adams JL, Nuttall ME, Nadeau DP, Kikly K, Winkler JD, Sung CM, Ryan MD, Levy MA, Keller PM, DeWolf WE Jr

Potent and selective nonpeptide inhibitors of caspases 3 and 7.

J Med Chem. 2001 Jun 7;44(12):2015-26.

PubMed ID

11384246 [ View in PubMed

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Abstract

5-Dialkylaminosulfonylisatins have been identified as potent, nonpeptide inhibitors 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 approximately 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 versus caspase 9. Sequence alignments of the active site residues of the caspases strongly suggest that the basis of this selectivity is due to binding in the S2 subsite comprised of residues Tyr204, Trp206, and Phe256 which are unique to caspases 3 and 7. These compounds inhibit apoptosis in three cell-based models: human Jurkat T cells, human chondrocytes, and mouse bone marrow neutrophils.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
1-METHYL-5-(2-PHENOXYMETHYL-PYRROLIDINE-1-SULFONYL)-1H-INDOLE-2,3-DIONE	Caspase-3	IC 50 (nM)	30	7.5	30	Details