Fragment-based drug discovery of potent and selective MKK3/6 inhibitors

Bioorg Med Chem Lett. 2016 Feb 1;26(3):1086-1089. doi: 10.1016/j.bmcl.2015.11.054. Epub 2015 Nov 17.

Abstract

The MAPK signaling cascade, comprised of several linear and intersecting pathways, propagates signaling into the nucleus resulting in cytokine and chemokine release. The Map Kinase Kinase isoforms 3 and 6 (MKK3 and MKK6) are responsible for the phosphorylation and activation of p38, and are hypothesized to play a key role in regulating this pathway without the redundancy seen in downstream effectors. Using FBDD, we have discovered efficient and selective inhibitors of MKK3 and MKK6 that can serve as tool molecules to help further understand the role of these kinases in MAPK signaling, and the potential impact of inhibiting kinases upstream of p38.

Keywords: FBDD; MAP Kinase Kinase 3 (MKK3); MAP Kinase Kinase 6 (MKK6).

MeSH terms

  • Binding Sites
  • Drug Design*
  • Humans
  • MAP Kinase Kinase 3 / antagonists & inhibitors*
  • MAP Kinase Kinase 3 / metabolism
  • MAP Kinase Kinase 6 / antagonists & inhibitors*
  • MAP Kinase Kinase 6 / metabolism
  • MAP Kinase Signaling System / drug effects
  • Molecular Docking Simulation
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Protein Structure, Tertiary
  • U937 Cells
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Protein Kinase Inhibitors
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 3
  • MAP Kinase Kinase 6
  • MAP2K3 protein, human
  • MAP2K6 protein, human