title: Mechanistic and structural understanding of uncompetitive inhibitors of caspase-6.
abstract: Inhibition of caspase-6 is a potential therapeutic strategy for some neurodegenerative diseases, but it has been difficult to develop selective inhibitors against caspases. We report the discovery and characterization of a potent inhibitor of caspase-6 that acts by an uncompetitive binding mode that is an unprecedented mechanism of inhibition against this target class. Biochemical assays demonstrate that, while exquisitely selective for caspase-6 over caspase-3 and -7, the compound's inhibitory activity is also dependent on the amino acid sequence and P1' character of the peptide substrate. The crystal structure of the ternary complex of caspase-6, substrate-mimetic and an 11 nM inhibitor reveals the molecular basis of inhibition. The general strategy to develop uncompetitive inhibitors together with the unique mechanism described herein provides a rationale for engineering caspase selectivity.
authors.affiliation: Department of Biochemical and Cellular Pharmacology, Genentech, Inc, South San Francisco, California, United States of America. heise.christopher@gene.com
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Heise
authors.forename: Jeremy
authors.initials: J
authors.lastname: Murray
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Augustyn
authors.forename: Brandon
authors.initials: B
authors.lastname: Bravo
authors.forename: Preeti
authors.initials: P
authors.lastname: Chugha
authors.forename: Frederick
authors.initials: F
authors.lastname: Cohen
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Giannetti
authors.forename: Paul
authors.initials: P
authors.lastname: Gibbons
authors.forename: Rami N
authors.initials: RN
authors.lastname: Hannoush
authors.forename: Brian R
authors.initials: BR
authors.lastname: Hearn
authors.forename: Priyadarshini
authors.initials: P
authors.lastname: Jaishankar
authors.forename: Cuong Q
authors.initials: CQ
authors.lastname: Ly
authors.forename: Kinjalkumar
authors.initials: K
authors.lastname: Shah
authors.forename: Karen
authors.initials: K
authors.lastname: Stanger
authors.forename: Micah
authors.initials: M
authors.lastname: Steffek
authors.forename: Yinyan
authors.initials: Y
authors.lastname: Tang
authors.forename: Xianrui
authors.initials: X
authors.lastname: Zhao
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Lewcock
authors.forename: Adam R
authors.initials: AR
authors.lastname: Renslo
authors.forename: John
authors.initials: J
authors.lastname: Flygare
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Arkin
mesh_terms: D000595:Amino Acid Sequence; D053178:Caspase 6 / Q000737:chemistry / Q000378:metabolism*; D061945:Caspase Inhibitors / Q000032:analysis / Q000737:chemistry* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D015203:Reproducibility of Results; D013379:Substrate Specificity / Q000187:drug effects; D020349:Surface Plasmon Resonance
chemical_list: D061945:Caspase Inhibitors; D010455:Peptides; D053178:Caspase 6