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

L. Meijer, A. M W H Thunnissen, A. W. White, M. Garnier, M. Nikolic, L. H. Tsai, J. Walter, K. E. Cleverley, P. C. Salinas, Y. Z. Wu, J. Biernat, E. M. Mandelkow, S. H. Kim, George Pettit

Research output: Contribution to journalArticle

380 Citations (Scopus)

Abstract

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-3β 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-1 B 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.

Original languageEnglish (US)
Pages (from-to)51-63
Number of pages13
JournalChemistry and Biology
Volume7
Issue number1
DOIs
StatePublished - Jan 1 2000

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Cyclin-Dependent Kinase 3
Glycogen Synthase Kinase 3
Cyclin-Dependent Kinases
Porifera
Phosphorylation
Phosphotransferases
Casein Kinase I
Microtubule Proteins
hymenialdisine
Inhibition (Psychology)
Biological Products
Neurodegenerative Diseases
Protein Kinases
Neurons
Rats
Hydrogen
Carrier Proteins
Hydrogen bonds
Alzheimer Disease
Screening

Keywords

  • Alzheimer's disease
  • Cyclin-dependent kinases
  • Glycogen synthase kinase
  • Hymenialdisine
  • Tau

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Inhibition of cyclin-dependent kinases, GSK-3β and CK1 by hymenialdisine, a marine sponge constituent. / Meijer, L.; Thunnissen, A. M W H; White, A. W.; Garnier, M.; Nikolic, M.; Tsai, L. H.; Walter, J.; Cleverley, K. E.; Salinas, P. C.; Wu, Y. Z.; Biernat, J.; Mandelkow, E. M.; Kim, S. H.; Pettit, George.

In: Chemistry and Biology, Vol. 7, No. 1, 01.01.2000, p. 51-63.

Research output: Contribution to journalArticle

Meijer, L, Thunnissen, AMWH, White, AW, Garnier, M, Nikolic, M, Tsai, LH, Walter, J, Cleverley, KE, Salinas, PC, Wu, YZ, Biernat, J, Mandelkow, EM, Kim, SH & Pettit, G 2000, 'Inhibition of cyclin-dependent kinases, GSK-3β and CK1 by hymenialdisine, a marine sponge constituent', Chemistry and Biology, vol. 7, no. 1, pp. 51-63. https://doi.org/10.1016/S1074-5521(00)00063-6
Meijer, L. ; Thunnissen, A. M W H ; White, A. W. ; Garnier, M. ; Nikolic, M. ; Tsai, L. H. ; Walter, J. ; Cleverley, K. E. ; Salinas, P. C. ; Wu, Y. Z. ; Biernat, J. ; Mandelkow, E. M. ; Kim, S. H. ; Pettit, George. / Inhibition of cyclin-dependent kinases, GSK-3β and CK1 by hymenialdisine, a marine sponge constituent. In: Chemistry and Biology. 2000 ; Vol. 7, No. 1. pp. 51-63.
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AU - Nikolic, M.

AU - Tsai, L. H.

AU - Walter, J.

AU - Cleverley, K. E.

AU - Salinas, P. C.

AU - Wu, Y. Z.

AU - Biernat, J.

AU - Mandelkow, E. M.

AU - Kim, S. H.

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