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.
Meijer
L
L
CNRS, Station Biologique, Roscoff cedex, 29682, France. meijer@sb-roscoff.fr
Thunnissen
A M
AM
White
A W
AW
Garnier
M
M
Nikolic
M
M
Tsai
L H
LH
Walter
J
J
Cleverley
K E
KE
Salinas
P C
PC
Wu
Y Z
YZ
Biernat
J
J
Mandelkow
E M
EM
Kim
S H
SH
Pettit
G R
GR
D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors; D000818:Animals; D001381:Azepines / Q000494:pharmacology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D047388:Casein Kinases; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D003460:Crystallization; D018360:Crystallography, X-Ray; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008968:Molecular Conformation; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D010766:Phosphorylation; D011161:Porifera / Q000737:chemistry*; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000737:chemistry; D011758:Pyrroles / Q000494:pharmacology*; D016875:tau Proteins / Q000378:metabolism
D001381:Azepines; D008869:Microtubule-Associated Proteins; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; C085284:microtubule-associated protein 1B; D016875:tau Proteins; D000255:Adenosine Triphosphate; C107079:hymenialdisine; D011494:Protein Kinases; D038341:Glycogen Synthase Kinases; D047388:Casein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D018844:Cyclin-Dependent Kinases; D038362:Glycogen Synthase Kinase 3