Novel MK2 inhibitors by fragment screening

Comb Chem High Throughput Screen. 2009 Aug;12(7):697-703. doi: 10.2174/138620709788923700. Epub 2009 Aug 1.


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.

MeSH terms

  • Biological Assay / methods*
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Peptide Fragments* / genetics
  • Peptide Fragments* / metabolism
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Signal Transduction
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / metabolism


  • Enzyme Inhibitors
  • Intracellular Signaling Peptides and Proteins
  • Peptide Fragments
  • Tumor Necrosis Factor-alpha
  • MAP-kinase-activated kinase 2
  • Protein Serine-Threonine Kinases