Identification of potent and selective small-molecule inhibitors of caspase-3 through the use of extended tethering and structure-based drug design

…, JW Lam, C Wiesmann, TN Luong, B Fahr…

文献索引：Choong, Ingrid C.; Lew, Willard; Lee, Dennis; Pham, Phuongly; Burdett, Matthew T.; Lam, Joni W.; Wiesmann, Christian; Luong, Tinh N.; Fahr, Bruce; DeLano, Warren L.; McDowell, Robert S.; Allen, Darin A.; Erlanson, Daniel A.; Gordon, Eric M.; O'Brien, Tom Journal of Medicinal Chemistry, 2002 , vol. 45, # 23 p. 5005 - 5022

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被引用次数: 122

摘要

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 S4 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 ...