Discovery of a potent and highly selective PDK1 inhibitor via fragment-based drug discovery

Bioorg Med Chem Lett. 2011 May 15;21(10):3078-83. doi: 10.1016/j.bmcl.2011.03.032. Epub 2011 Mar 17.

Abstract

We report the use of a fragment-based lead discovery method, Tethering with extenders, to discover a pyridinone fragment that binds in an adaptive site of the protein PDK1. With subsequent medicinal chemistry, this led to the discovery of a potent and highly selective inhibitor of PDK1, which binds in the 'DFG-out' conformation.

MeSH terms

  • Crystallography, X-Ray
  • Drug Design*
  • Drug Discovery
  • Enzyme Activation / drug effects*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Inhibitory Concentration 50
  • Models, Biological
  • Molecular Structure
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Pyridones / chemistry
  • Pyridones / pharmacology
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • Small Molecule Libraries / chemistry*
  • Small Molecule Libraries / pharmacology
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Pyridones
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • Small Molecule Libraries
  • Protein Serine-Threonine Kinases

Associated data

  • PDB/3QC4