273216-04-9Relevant articles and documents
Solid phase synthesis of selective caspase-3 peptide inhibitors
Grimm, Erich L.,Roy, Bruno,Aspiotis, Renee,Bayly, Christopher I.,Nicholson, Donald W.,Rasper, Dita M.,Renaud, Johanne,Roy, Sophie,Tam, John,Tawa, Paul,Vaillancourt, John P.,Xanthoudakis, Steven,Zamboni, Robert J.
, p. 845 - 851 (2007/10/03)
A robust method for the solid phase synthesis of a series of selective caspase-3 peptide inhibitors is described. The inhibitors can be obtained after cleavage from the solid support without further purification.
Identification of potent and selective small-molecule inhibitors of caspase-3 through the use of extended tethering and structure-based drug design
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
, p. 5005 - 5022 (2007/10/03)
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 Ki = 40 nM. Further optimization led to the identification of a series of potent and selective inhibitors with Ki values in the 20-50 nM range. One of the most potent compounds in this series, 66b, inhibited caspase-3 with a Ki = 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.
