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.

Frizzled 8a function is required for oligodendrocyte development in the zebrafish spinal cord

“…We used 6-bromoindirubin-3Ј-oxime (Bio), a specific inhibitor of glycogen synthase kinase-3 (Sato et al, 2004;Atilla-Gokcumen et al, 2006), and lithium chloride (LiCl), a stimulator of the ␤-cateninmediated class I Wnt signaling pathway (Klein and Melton, 1996). We first tested whether Bio and LiCl could activate Wnt signaling in zebrafish embryos.…”

Cysteine‐Specific, Covalent Anchoring of Transition Organometallic Complexes to the Protein Papain from Carica papaya

“…[19][20][21] Another possibility is to design heavy-atom-laA C H T U N G T R E N N U N G belled inhibitors of enzymes. [22][23][24][25] During the past ten years, we have designed and prepared several families of transition organometallic complexes for the side-chain specific and covalent labelling of proteins, and studied their reactivity with, inter alia, bovine serum albumin (BSA), hen egg white lysozyme (HEWL) or avidin. [26,27] Most of these reagents targeted the protein primary amines borne by lysine residues and the N-terminal amino acid.…”

Ca2+/Calmodulin-dependent Protein Kinase Kinase β Is Regulated by Multisite Phosphorylation

“…To test if CaMKK␤ is phosphorylated by GSK3, we inhibited GSK3 activity using the GSK3 inhibitor XV compound (33). After an overnight treatment of the cells with 0.1 M of the GSK3 inhibitor, all reactivity with the phosphoserine antibody was lost (Fig.…”