Organometallic Compounds with Biological Activity: A Very Selective and Highly Potent Cellular Inhibitor for Glycogen Synthase Kinase 3

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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 μM 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.