Organometallic compounds with biological activity: a very selective and highly potent cellular inhibitor for glycogen synthase kinase 3

Chembiochem. 2006 Sep;7(9):1443-50. doi: 10.1002/cbic.200600117.

Abstract

A chiral second-generation organoruthenium half-sandwich compound is disclosed that shows a remarkable selectivity and cellular potency for the inhibition of glycogen synthase kinase 3 (GSK-3). The selectivity was evaluated against a panel of 57 protein kinases, in which no other kinase was inhibited to the same extent, with a selectivity window of at least tenfold to more than 1000-fold at 100 microM ATP. Furthermore, a comparison with organic GSK-3 inhibitors demonstrated the superior cellular activity of this ruthenium compound: wnt signaling was fully induced at concentrations down to 30 nM. For comparison, the well-established organic GSK-3 inhibitors 6-bromoindirubin-3'-oxime (BIO) and kenpaullone activate the wnt pathway at concentrations that are higher by around 30-fold and 100-fold, respectively. The treatment of zebrafish embryos with the organometallic inhibitor resulted in a phenotype that is typical for the inhibition of GSK-3. No phenotypic change was observed with the mirror-imaged ruthenium complex. The latter does not, in fact, show any of the pharmacological properties for the inhibition of GSK-3. Overall, these results demonstrate the potential usefulness of organometallic compounds as molecular probes in cultured cells and whole organisms.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Catalysis
  • Cell Line
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Embryo, Nonmammalian / abnormalities
  • Embryo, Nonmammalian / drug effects
  • Embryo, Nonmammalian / metabolism
  • Gene Expression / drug effects
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors*
  • Glycogen Synthase Kinase 3 / chemistry
  • HeLa Cells
  • Humans
  • Molecular Structure
  • Organometallic Compounds / chemical synthesis
  • Organometallic Compounds / chemistry*
  • Organometallic Compounds / pharmacology
  • Phenotype
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinases / chemistry
  • Ruthenium / chemistry
  • Stereoisomerism
  • TCF Transcription Factors / genetics
  • TCF Transcription Factors / metabolism
  • Zebrafish
  • beta Catenin / metabolism

Substances

  • Organometallic Compounds
  • Protein Kinase Inhibitors
  • TCF Transcription Factors
  • beta Catenin
  • Ruthenium
  • Protein Kinases
  • Glycogen Synthase Kinase 3