title: Small-molecule inhibition of TNF-alpha.
abstract: We have identified a small-molecule inhibitor of tumor necrosis factor alpha (TNF-alpha) that promotes subunit disassembly of this trimeric cytokine family member. The compound inhibits TNF-alpha activity in biochemical and cell-based assays with median inhibitory concentrations of 22 and 4.6 micromolar, respectively. Formation of an intermediate complex between the compound and the intact trimer results in a 600-fold accelerated subunit dissociation rate that leads to trimer dissociation. A structure solved by x-ray crystallography reveals that a single compound molecule displaces a subunit of the trimer to form a complex with a dimer of TNF-alpha subunits.
authors.affiliation: Sunesis Pharmaceuticals, Incorporated, 341 Oyster Point Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Molly M
authors.initials: MM
authors.lastname: He
authors.forename: Annemarie Stroustrup
authors.initials: AS
authors.lastname: Smith
authors.forename: Johan D
authors.initials: JD
authors.lastname: Oslob
authors.forename: William M
authors.initials: WM
authors.lastname: Flanagan
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Braisted
authors.forename: Adrian
authors.initials: A
authors.lastname: Whitty
authors.forename: Mark T
authors.initials: MT
authors.lastname: Cancilla
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Alexey A
authors.initials: AA
authors.lastname: Lugovskoy
authors.forename: Josh C
authors.initials: JC
authors.lastname: Yoburn
authors.forename: Amy D
authors.initials: AD
authors.lastname: Fung
authors.forename: Graham
authors.initials: G
authors.lastname: Farrington
authors.forename: John K
authors.initials: JK
authors.lastname: Eldredge
authors.forename: Eric S
authors.initials: ES
authors.lastname: Day
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Cruz
authors.forename: Teresa G
authors.initials: TG
authors.lastname: Cachero
authors.forename: Stephan K
authors.initials: SK
authors.lastname: Miller
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Friedman
authors.forename: Ingrid C
authors.initials: IC
authors.lastname: Choong
authors.forename: Brian C
authors.initials: BC
authors.lastname: Cunningham
mesh_terms: D019921:Biotinylation; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D018360:Crystallography, X-Ray; D019281:Dimerization; D005453:Fluorescence; D006859:Hydrogen / Q000737:chemistry; D057927:Hydrophobic and Hydrophilic Interactions; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D007700:Kinetics; D013058:Mass Spectrometry; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D011487:Protein Conformation; D021122:Protein Subunits / Q000737:chemistry; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism
chemical_list: D007211:Indoles; D021122:Protein Subunits; D047888:Receptors, Tumor Necrosis Factor, Type I; C505854:SPD00000304; D014409:Tumor Necrosis Factor-alpha; D006859:Hydrogen