title: Tethering identifies fragment that yields potent inhibitors of human caspase-1.
abstract: 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.
authors.affiliation: Department of Chemistry, Sunesis Pharmaceuticals, 341 Oyster Point Boulevard, South San Francisco, CA 94080, USA. bfahr@sunesis.com
authors.forename: Bruce T
authors.initials: BT
authors.lastname: Fahr
authors.forename: Tom
authors.initials: T
authors.lastname: O'Brien
authors.forename: Phuongly
authors.initials: P
authors.lastname: Pham
authors.forename: Nathan D
authors.initials: ND
authors.lastname: Waal
authors.forename: Subramanian
authors.initials: S
authors.lastname: Baskaran
authors.forename: Brian C
authors.initials: BC
authors.lastname: Raimundo
authors.forename: Joni W
authors.initials: JW
authors.lastname: Lam
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Sopko
authors.forename: Hans E
authors.initials: HE
authors.lastname: Purkey
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Romanowski
mesh_terms: 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
chemical_list: D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D020170:Caspase 1