Discovery of 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine inhibitors of Erk2

Bioorg Med Chem Lett. 2014 Jun 15;24(12):2635-9. doi: 10.1016/j.bmcl.2014.04.068. Epub 2014 Apr 29.

Abstract

The discovery and optimization of a series of tetrahydropyridopyrimidine based extracellular signal-regulated kinase (Erks) inhibitors discovered via HTS and structure based drug design is reported. The compounds demonstrate potent and selective inhibition of Erk2 and knockdown of phospho-RSK levels in HepG2 cells and tumor xenografts.

Keywords: Erk2 kinase inhibitors; Mek resistance; Structure based drug design.

MeSH terms

  • Cell Line, Tumor
  • Combinatorial Chemistry Techniques
  • Crystallography, X-Ray
  • Drug Discovery*
  • Enzyme Activation / drug effects
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors*
  • Hep G2 Cells
  • Humans
  • Inhibitory Concentration 50
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology
  • Pyridines / chemical synthesis*
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Small Molecule Libraries
  • Structure-Activity Relationship

Substances

  • 6-(2,5-dimethoxybenzyl)-5,6,7,8-tetrahydropyrido(2,3-d)pyrimidine-2,4-diamine
  • Protein Kinase Inhibitors
  • Pyridines
  • Pyrimidines
  • Small Molecule Libraries
  • Extracellular Signal-Regulated MAP Kinases