Tethering identifies fragment that yields potent inhibitors of human caspase-1.
Disulfide Tethering was applied to the active site of human caspase-1, resulting in the discovery of a novel, tricyclic molecular fragment that selectively binds in S4. This fragment was developed into a class of potent inhibitors of human caspase-1. Several key analogues determined the optimal distance of the tricycle from the catalytic residues, the relative importance of various features of the tricycle, and the importance of the linker.
Fahr
Bruce T
BT
Department of Chemistry, Sunesis Pharmaceuticals, 341 Oyster Point Boulevard, South San Francisco, CA 94080, USA. bfahr@sunesis.com
O'Brien
Tom
T
Pham
Phuongly
P
Waal
Nathan D
ND
Baskaran
Subramanian
S
Raimundo
Brian C
BC
Lam
Joni W
JW
Sopko
Michelle M
MM
Purkey
Hans E
HE
Romanowski
Michael J
MJ
D001665:Binding Sites; D020170:Caspase 1 / Q000737:chemistry; D061945:Caspase Inhibitors; D002384:Catalysis; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006575:Heterocyclic Compounds, 3-Ring / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D013329:Structure-Activity Relationship
D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D020170:Caspase 1