title: Organometallic compounds with biological activity: a very selective and highly potent cellular inhibitor for glycogen synthase kinase 3.
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.
authors.affiliation: Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, PA 19104, USA.
authors.forename: G Ekin
authors.initials: GE
authors.lastname: Atilla-Gokcumen
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Williams
authors.forename: Howard
authors.initials: H
authors.lastname: Bregman
authors.forename: Nicholas
authors.initials: N
authors.lastname: Pagano
authors.forename: Eric
authors.initials: E
authors.lastname: Meggers
mesh_terms: D000818:Animals; D002384:Catalysis; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004625:Embryo, Nonmammalian / Q000002:abnormalities / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006367:HeLa Cells; D006801:Humans; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011494:Protein Kinases / Q000737:chemistry; D012428:Ruthenium / Q000737:chemistry; D013237:Stereoisomerism; D051820:TCF Transcription Factors / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish; D051176:beta Catenin / Q000378:metabolism
chemical_list: D009942:Organometallic Compounds; D047428:Protein Kinase Inhibitors; D051820:TCF Transcription Factors; D051176:beta Catenin; D012428:Ruthenium; D011494:Protein Kinases; D038362:Glycogen Synthase Kinase 3