title: TAK1 inhibition in the DFG-out conformation.
abstract: The first example of an inhibitor of the kinase TAK1 that binds in the DFG-out conformation is disclosed. These preliminary studies used kinase-targeted screening and structure-based drug design to create a molecule with dual pharmacological inhibition of p38 and TAK1 that demonstrated significant activity in a cell-based, anti-inflammatory assay.
authors.affiliation: Pfizer World Wide Research and Development, Ramsgate Road, Sandwich, CT13 9NJ, UK; BioTherapeutics Research and Development, Pfizer, Cambridge, MA, 02140, USA.
authors.forename: Iain
authors.initials: I
authors.lastname: Kilty
authors.forename: Martin P
authors.initials: MP
authors.lastname: Green
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Bell
authors.forename: David G
authors.initials: DG
authors.lastname: Brown
authors.forename: Peter G
authors.initials: PG
authors.lastname: Dodd
authors.forename: Christopher
authors.initials: C
authors.lastname: Hewson
authors.forename: Samantha J
authors.initials: SJ
authors.lastname: Hughes
authors.forename: Christopher
authors.initials: C
authors.lastname: Phillips
authors.forename: Thomas
authors.initials: T
authors.lastname: Ryckmans
authors.forename: Robert T
authors.initials: RT
authors.lastname: Smith
authors.forename: Willem P
authors.initials: WP
authors.lastname: van Hoorn
authors.forename: Philip
authors.initials: P
authors.lastname: Cohen
authors.forename: Lyn H
authors.initials: LH
authors.lastname: Jones
mesh_terms: D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D000893:Anti-Inflammatory Agents; D008070:Lipopolysaccharides; D020930:MAP Kinase Kinase Kinases; D047428:Protein Kinase Inhibitors; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7
keywords: X-ray crystallography; chemical biology; drug design; kinase; phosphatase; structure-based drug design