Thieno[3,2-d]pyrimidin-4(3H)-one derivatives as PDK1 inhibitors discovered by fragment-based screening

Bioorg Med Chem Lett. 2012 Jun 15;22(12):4023-7. doi: 10.1016/j.bmcl.2012.04.080. Epub 2012 Apr 25.

Abstract

Ligand efficient fragments binding to PDK1 were identified by an NMR fragment-based screening approach. Computational modeling of the fragments bound to the active site led to the design and synthesis of a series of novel 6,7-disubstituted thienopyrimidin-4-one compounds, with low micromolar inhibitory activity against PDK1 in a biochemical enzyme assay.

MeSH terms

  • 3-Phosphoinositide-Dependent Protein Kinases
  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology
  • Catalytic Domain
  • Computer Simulation
  • Drug Design
  • Humans
  • Kinetics
  • Ligands
  • Magnetic Resonance Spectroscopy
  • Mice
  • Models, Molecular
  • Protein Binding
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / pharmacology
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein Serine-Threonine Kinases / metabolism
  • Pyrimidinones / chemical synthesis*
  • Pyrimidinones / pharmacology

Substances

  • Antineoplastic Agents
  • Ligands
  • Protein Kinase Inhibitors
  • Pyrimidinones
  • 3-Phosphoinositide-Dependent Protein Kinases
  • PDPK1 protein, human
  • Pdpk1 protein, mouse
  • Protein Serine-Threonine Kinases