title: Identification of potent and selective small-molecule inhibitors of caspase-3 through the use of extended tethering and structure-based drug design.
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.
authors.affiliation: Sunesis Pharmaceuticals, Inc., 341 Oyster Point Boulevard, South San Francisco, California 94080, USA. ichoong@sunesis.com
authors.forename: Ingrid C
authors.initials: IC
authors.lastname: Choong
authors.forename: Willard
authors.initials: W
authors.lastname: Lew
authors.forename: Dennis
authors.initials: D
authors.lastname: Lee
authors.forename: Phuongly
authors.initials: P
authors.lastname: Pham
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Burdett
authors.forename: Joni W
authors.initials: JW
authors.lastname: Lam
authors.forename: Christian
authors.initials: C
authors.lastname: Wiesmann
authors.forename: Tinh N
authors.initials: TN
authors.lastname: Luong
authors.forename: Bruce
authors.initials: B
authors.lastname: Fahr
authors.forename: Warren L
authors.initials: WL
authors.lastname: DeLano
authors.forename: Robert S
authors.initials: RS
authors.lastname: McDowell
authors.forename: Darin A
authors.initials: DA
authors.lastname: Allen
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Erlanson
authors.forename: Eric M
authors.initials: EM
authors.lastname: Gordon
authors.forename: Tom
authors.initials: T
authors.lastname: O'Brien
mesh_terms: D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry; D001583:Benzoxazoles / Q000138:chemical synthesis / Q000737:chemistry; D001665:Binding Sites; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000737:chemistry; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D005449:Fluorenes / Q000138:chemical synthesis / Q000737:chemistry; D006801:Humans; D011485:Protein Binding; D012459:Salicylates / Q000138:chemical synthesis* / Q000737:chemistry; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry
chemical_list: C468788:5-((5-(1-carboxymethyl-3-(2-chlorobenzylsulfanyl)-2-oxopropylcarbamoyl)thiophen-2-ylmethyl)sulfamoyl)-2-hydroxybenzoic acid; D001583:Benzoxazoles; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D005449:Fluorenes; D012459:Salicylates; D013449:Sulfonamides; D013876:Thiophenes; D001224:Aspartic Acid; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases