Identification of Potent and Selective Small-Molecule Inhibitors of Caspase-3 through the Use of Extended Tethering and Structure-Based Drug Design

Sunesis Pharmaceuticals, Inc., 341 Oyster Point Boulevard, South San Francisco, California 94080, USA.
Journal of Medicinal Chemistry (Impact Factor: 5.45). 12/2002; 45(23):5005-22. DOI: 10.1021/jm020230j
Source: PubMed


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.

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    • "All of the above studies are available on different nuclei and BioMed Research International different caspase-3 PDB IDs, but till now no study is available on pyrrolo[3,4-c]quinoline-1,3-diones using PDB ID: 1GFW. Generally, potent caspase-3 inhibitors reported till date are peptides in nature [14] [15] [16] [17]. However, such inhibitors often acquire poor cell permeability and low metabolic stability [18]. "
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