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


BACKGROUND Over 2000 protein kinases regulate cellular functions. Screening for inhibitors of some of these kinases has already yielded some potent and 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-3beta and casein kinase 1. Hymenialdisine competes with ATP for binding to these kinases. A CDK2-hymenialdisine complex crystal structure shows that three hydrogen bonds link hymenialdisine to the Glu81 and Leu83 residues of CDK2, as observed with other inhibitors. Hymenialdisine inhibits CDK5/p35 in vivo as demonstrated by the lack of phosphorylation/down-regulation of Pak1 kinase in E18 rat cortical neurons, and also inhibits GSK-3 in vivo as shown by the inhibition of MAP-1B phosphorylation. Hymenialdisine also blocks the in vivo phosphorylation of the microtubule-binding protein tau at sites that are hyperphosphorylated by GSK-3 and CDK5/p35 in Alzheimer's disease (cross-reacting with Alzheimer's-specific AT100 antibodies). CONCLUSIONS The natural product hymenialdisine is a new kinase inhibitor with promising potential applications for treating neurodegenerative disorders.

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@article{Meijer2000InhibitionOC, title={Inhibition of cyclin-dependent kinases, GSK-3beta and CK1 by hymenialdisine, a marine sponge constituent.}, author={Laurent Meijer and Andy Mark W H Thunnissen and Alex W White and Micka{\"{e}l Garnier and Margareta Nikoli{\'c} and Li Huei Tsai and J{\"{o}rn Walter and Karen E Cleverley and Patricia Salinas and Yong Zhuo Wu and Jacek Biernat and E . - M . Mandelkow and S Kim and George R. Pettit}, journal={Chemistry & biology}, year={2000}, volume={7 1}, pages={51-63} }