title: Discovery and characterization of MAPK-activated protein kinase-2 prevention of activation inhibitors.
abstract: Two structurally distinct series of novel, MAPK-activated kinase-2 prevention of activation inhibitors have been discovered by high throughput screening. Preliminary structure-activity relationship (SAR) studies revealed substructural features that influence the selective inhibition of the activation by p38α of the downstream kinase MK2 in preference to an alternative substrate, MSK1. Enzyme kinetics, surface plasmon resonance (SPR), 2D protein NMR, and X-ray crystallography were used to determine the binding mode and the molecular mechanism of action. The compounds bind competitively to the ATP binding site of p38α but unexpectedly with higher affinity in the p38α-MK2 complex compared with p38α alone. This observation is hypothesized to be the origin of the substrate selectivity. The two lead series identified are suitable for further investigation for their potential to treat chronic inflammatory diseases with improved tolerability over previously studied p38α inhibitors.
authors.affiliation: AstraZeneca , Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: John G
authors.initials: JG
authors.lastname: Cumming
authors.forename: Judit É
authors.initials: JÉ
authors.lastname: Debreczeni
authors.forename: Fredrik
authors.initials: F
authors.lastname: Edfeldt
authors.forename: Emma
authors.initials: E
authors.lastname: Evertsson
authors.forename: Martin
authors.initials: M
authors.lastname: Harrison
authors.forename: Geoffrey A
authors.initials: GA
authors.lastname: Holdgate
authors.forename: Michael J
authors.initials: MJ
authors.lastname: James
authors.forename: Scott G
authors.initials: SG
authors.lastname: Lamont
authors.forename: Keith
authors.initials: K
authors.lastname: Oldham
authors.forename: Jane E
authors.initials: JE
authors.lastname: Sullivan
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Wells
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D001667:Binding, Competitive; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D020349:Surface Plasmon Resonance
chemical_list: D047428:Protein Kinase Inhibitors; D000255:Adenosine Triphosphate; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C116919:mitogen and stress-activated protein kinase 1; D048308:Mitogen-Activated Protein Kinase 14; D048370:MAP Kinase Kinase 2