Inhibition of cyclin-dependent kinases, GSK-3 beta and CK1 by hymenialdisine, a marine sponge constituent

Background: Over 2000 protein kinases regulate cellular functions. Screenin g for inhibitors of some of these kinases has already yielded some potent a nd selective compounds with promising potential for the treatment of human diseases. Results: The marine sponge constituent hymenialdisine is a potent inhibitor of cyclin-dependent kinases, glycogen synthase kinase-3 beta and casein ki nase 1. Hymenialdisine competes with ATP for binding to these kinases, A CD K2-hymenialdisine complex crystal structure shows that three hydrogen bonds link hymenialdisine to the Glu81 and Leu83 residues of CDK2, as observed w ith other inhibitors. Hymenialdisine inhibits CDK5/p35 in vivo as demonstra ted by the lack of phosphorylation/down-regulation of Pak1 kinase in E18 ra t cortical neurons, and also inhibits GSK-3 in vivo as shown by the inhibit ion of MAP-1B phosphorylation, Hymenialdisine also blocks the in vivo phosp horylation of the microtubule-binding protein tau at sites that are hyperph osphorylated by GSK-3 and CDK5/p35 in Alzheimer's disease (cross-reacting w ith Alzheimer's-specific AT100 antibodies). Conclusions: The natural product hymenialdisine is a new kinase inhibitor w ith promising potential applications for treating neurodegenerative disorde rs.