title: Novel MK2 inhibitors by fragment screening.
abstract: Inhibitors of MAPKAP kinase 2 (MK2) are expected to attenuate the p38alpha signal transduction pathway in macrophages in a similar way to p38alpha inhibitors and to have a lower propensity for toxic side effects that have slowed the clinical development of the latter. Therefore, novel MK2 inhibitors may find therapeutic application in acute and chronic, TNFalpha-mediated inflammatory conditions like rheumatoid arthritis and others. Herein we have applied fragment screening, using physiologically relevant bioassays and fragment binding mode mapping by protein-observed NMR spectroscopy to the discovery of novel efficient chemical starting points for MK2.
authors.affiliation: Evotec AG, Hamburg, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Keminer
authors.forename: Joachim
authors.initials: J
authors.lastname: Kraemer
authors.forename: Jan
authors.initials: J
authors.lastname: Kahmann
authors.forename: Ina
authors.initials: I
authors.lastname: Sternberger
authors.forename: Christoph
authors.initials: C
authors.lastname: Scheich
authors.forename: Joern
authors.initials: J
authors.lastname: Jungmann
authors.forename: Sabine
authors.initials: S
authors.lastname: Schaert
authors.forename: Dirk
authors.initials: D
authors.lastname: Winkler
authors.forename: Osamu
authors.initials: O
authors.lastname: Ichihara
authors.forename: Mark
authors.initials: M
authors.lastname: Whittaker
authors.forename: Dirk
authors.initials: D
authors.lastname: Ullmann
authors.forename: Thomas
authors.initials: T
authors.lastname: Hesterkamp
mesh_terms: D001681:Biological Assay / Q000379:methods*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D010446:Peptide Fragments; D017346:Protein Serine-Threonine Kinases; D014409:Tumor Necrosis Factor-alpha; D000099190:MAP-Kinase-Activated Kinase 2