Abstract
The design, synthesis, and in vitro activities of a series of potent and selective small-molecule inhibitors of caspase-3 are described. From extended tethering, a salicylic acid fragment was identified as having binding affinity for the S(4) pocket of caspase-3. X-ray crystallography and molecular modeling of the initial tethering hit resulted in the synthesis of 4, which reversibly inhibited caspase-3 with a K(i) = 40 nM. Further optimization led to the identification of a series of potent and selective inhibitors with K(i) values in the 20-50 nM range. One of the most potent compounds in this series, 66b, inhibited caspase-3 with a K(i) = 20 nM and selectivity of 8-500-fold for caspase-3 vs a panel of seven caspases (1, 2, and 4-8). A high-resolution X-ray cocrystal structure of 4 and 66b supports the predicted binding modes of our compounds with caspase-3.
MeSH terms
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Aspartic Acid / analogs & derivatives
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Aspartic Acid / chemical synthesis*
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Aspartic Acid / chemistry
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Benzoxazoles / chemical synthesis
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Benzoxazoles / chemistry
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Binding Sites
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Caspase 3
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Caspase Inhibitors*
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Caspases / chemistry
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Crystallography, X-Ray
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Drug Design
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / chemistry
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Fluorenes / chemical synthesis
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Fluorenes / chemistry
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Humans
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Protein Binding
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Salicylates / chemical synthesis*
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Salicylates / chemistry
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Sulfonamides / chemical synthesis*
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Sulfonamides / chemistry
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Thiophenes / chemical synthesis
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Thiophenes / chemistry
Substances
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5-((5-(1-carboxymethyl-3-(2-chlorobenzylsulfanyl)-2-oxopropylcarbamoyl)thiophen-2-ylmethyl)sulfamoyl)-2-hydroxybenzoic acid
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Benzoxazoles
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Caspase Inhibitors
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Enzyme Inhibitors
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Fluorenes
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Salicylates
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Sulfonamides
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Thiophenes
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Aspartic Acid
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CASP3 protein, human
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Caspase 3
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Caspases