2-anilino-4-aryl-8H-purine derivatives as inhibitors of PDK1

Bioorg Med Chem Lett. 2012 Apr 15;22(8):2880-4. doi: 10.1016/j.bmcl.2012.02.058. Epub 2012 Feb 27.

Abstract

A series of 2-anilino substituted 4-aryl-8H-purines were prepared as potent inhibitors of PDK1, a serine-threonine kinase thought to play a role in the PI3K/Akt signaling pathway, a key mediator of cancer cell growth, survival and tumorigenesis. The synthesis, SAR and ADME properties of this series of compounds are discussed culminating in the discovery of compound 6 which possessed sub-micromolar cell proliferation activity and 65% oral bioavailability in mice.

MeSH terms

  • Aniline Compounds / chemistry*
  • Aniline Compounds / pharmacology
  • Animals
  • Cell Line, Tumor
  • Cells, Cultured
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Inhibitory Concentration 50
  • Mice
  • Molecular Structure
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Purines / chemistry*
  • Purines / pharmacology
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • Small Molecule Libraries / chemistry*
  • Small Molecule Libraries / pharmacology
  • Solubility

Substances

  • Aniline Compounds
  • Enzyme Inhibitors
  • PDK1 protein, human
  • Pdk1 protein, mouse
  • Purines
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • Small Molecule Libraries
  • Protein Serine-Threonine Kinases
  • aniline
  • purine