title: Biphenyl amide p38 kinase inhibitors 4: DFG-in and DFG-out binding modes.
abstract: The biphenyl amides (BPAs) are a series of p38alpha MAP kinase inhibitors. Compounds are able to bind to the kinase in either the DFG-in or DFG-out conformation, depending on substituents. X-ray, binding, kinetic and cellular data are shown, providing the most detailed comparison to date between potent compounds from the same chemical series that bind to different p38alpha conformations. DFG-out-binding compounds could be made more potent than DFG-in-binding compounds by increasing their size. Unexpectedly, compounds that bound to the DGF-out conformation showed diminished selectivity. The kinetics of binding to the isolated enzyme and the effects of compounds on cells were largely unaffected by the kinase conformation bound.
authors.affiliation: GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Angell
authors.forename: Tony D
authors.initials: TD
authors.lastname: Angell
authors.forename: Paul
authors.initials: P
authors.lastname: Bamborough
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Bamford
authors.forename: Chun-wa
authors.initials: CW
authors.lastname: Chung
authors.forename: Stuart G
authors.initials: SG
authors.lastname: Cockerill
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Flack
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Jones
authors.forename: Dramane I
authors.initials: DI
authors.lastname: Laine
authors.forename: Timothy
authors.initials: T
authors.lastname: Longstaff
authors.forename: Steve
authors.initials: S
authors.lastname: Ludbrook
authors.forename: Rosannah
authors.initials: R
authors.lastname: Pearson
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Smith
authors.forename: Penny A
authors.initials: PA
authors.lastname: Smee
authors.forename: Don O
authors.initials: DO
authors.lastname: Somers
authors.forename: Ann L
authors.initials: AL
authors.lastname: Walker
mesh_terms: D000577:Amides / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000596:Amino Acids / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D001713:Biphenyl Compounds / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D015195:Drug Design; D008070:Lipopolysaccharides / Q000494:pharmacology; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors*; D008968:Molecular Conformation; D015394:Molecular Structure; D009281:Naphthalenes / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D013329:Structure-Activity Relationship; D010671:Phenylurea Compounds
chemical_list: D000577:Amides; D000596:Amino Acids; D001713:Biphenyl Compounds; D008070:Lipopolysaccharides; D048308:Mitogen-Activated Protein Kinase 14; D009281:Naphthalenes; D011720:Pyrazoles; C452139:doramapimod; D010671:Phenylurea Compounds