Allosteric Akt (PKB) inhibitors: discovery and SAR of isozyme selective inhibitors

Bioorg Med Chem Lett. 2005 Feb 1;15(3):761-4. doi: 10.1016/j.bmcl.2004.11.011.

Abstract

This letter describes the development of two series of potent and selective allosteric Akt kinase inhibitors that display an unprecedented level of selectivity for either Akt1, Akt2 or both Akt1/Akt2. An iterative analog library synthesis approach quickly provided a highly selective Akt1/Akt2 inhibitor that induces apoptosis in tumor cells and inhibits Akt phosphorylation in vivo.

MeSH terms

  • Allosteric Regulation*
  • Apoptosis / drug effects
  • Enzyme Inhibitors / chemical synthesis*
  • Humans
  • Inhibitory Concentration 50
  • Isoenzymes / antagonists & inhibitors
  • Phosphorylation / drug effects
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / antagonists & inhibitors*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Quinoxalines / chemical synthesis
  • Quinoxalines / pharmacology
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Isoenzymes
  • Proto-Oncogene Proteins
  • Quinoxalines
  • AKT1 protein, human
  • AKT2 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt