Identification of potent and selective small-molecule inhibitors of caspase-3 through the use of extended tethering and structure-based drug design.
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.
Choong
Ingrid C
IC
Sunesis Pharmaceuticals, Inc., 341 Oyster Point Boulevard, South San Francisco, California 94080, USA. ichoong@sunesis.com
Lew
Willard
W
Lee
Dennis
D
Pham
Phuongly
P
Burdett
Matthew T
MT
Lam
Joni W
JW
Wiesmann
Christian
C
Luong
Tinh N
TN
Fahr
Bruce
B
DeLano
Warren L
WL
McDowell
Robert S
RS
Allen
Darin A
DA
Erlanson
Daniel A
DA
Gordon
Eric M
EM
O'Brien
Tom
T
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
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