2,4-Diaminopyrimidine MK2 inhibitors. Part I: Observation of an unexpected inhibitor binding mode

Bioorg Med Chem Lett. 2010 Jan 1;20(1):330-3. doi: 10.1016/j.bmcl.2009.10.102. Epub 2009 Oct 29.

Abstract

MK2 is a Ser/Thr kinase of significant interest as an anti-inflammatory drug discovery target. Here we describe the development of in vitro tools for the identification and characterization of MK2 inhibitors, including validation of inhibitor interactions with the crystallography construct and determination of the unique binding mode of 2,4-diaminopyrimidine inhibitors in the MK2 active site. Use of these tools in the optimization of a potent and selective inhibitor lead series is described in the accompanying Letter.

MeSH terms

  • Adenosine Triphosphate / chemistry
  • Anti-Inflammatory Agents / chemical synthesis
  • Anti-Inflammatory Agents / chemistry*
  • Anti-Inflammatory Agents / pharmacology
  • Binding Sites
  • Binding, Competitive
  • Computer Simulation
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein Serine-Threonine Kinases / metabolism
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry*
  • Pyrimidines / pharmacology
  • Structure-Activity Relationship

Substances

  • Anti-Inflammatory Agents
  • Intracellular Signaling Peptides and Proteins
  • Protein Kinase Inhibitors
  • Pyrimidines
  • 2,4-diaminopyrimidine
  • Adenosine Triphosphate
  • MAP-kinase-activated kinase 2
  • Protein Serine-Threonine Kinases