TY - JOUR
T1 - Paullones are potent inhibitors of glycogen synthase kinase-3β and cyclin-dependent kinase 5/p25
AU - Leost, Maryse
AU - Schultz, Christiane
AU - Link, Andreas
AU - Wu, Yong Zhong
AU - Biernat, Jacek
AU - Mandelkow, Eva Maria
AU - Bibb, James A.
AU - Snyder, Gretchen L.
AU - Greengard, Paul
AU - Zaharevitz, Daniel W.
AU - Gussio, Rick
AU - Senderowicz, Adrian M.
AU - Sausville, Edward A.
AU - Kunick, Conrad
AU - Meijer, Laurent
PY - 2000
Y1 - 2000
N2 - Paullones constitute a new family of benzazepinones with promising antitumoral properties. They were recently described as potent, ATP-competitive, inhibitors of the cell cycle regulating cyclin-dependent kinases (CDKs). We here report that paullones also act as very potent inhibitors of glycogen synthase kinase-3β (GSK-3β) (IC50: 4-80 nM) and the neuronal CDK5/p25 (IC50: 20-200 nM). These two enzymes are responsible for most of the hyperphosphorylation of the microtubule-binding protein tau, a feature observed in the brains of patients with Alzheimer's disease and other neurodegenerative 'taupathies'. Alsterpaullone, the most active paullone, was demonstrated to act by competing with ATP for binding to GSK-3β. Alsterpaullone inhibits the phosphorylation of tau in vivo at sites which are typically phosphorylated by GSK-3β in Alzheimer's disease. Alsterpaullone also inhibits the CDK5/p25-dependent phosphorylation of DARPP-32 in mouse striatum slices in vitro. This dual specificity of paullones may turn these compounds into very useful tools for the study and possibly treatment of neurodegenerative and proliferative disorders.
AB - Paullones constitute a new family of benzazepinones with promising antitumoral properties. They were recently described as potent, ATP-competitive, inhibitors of the cell cycle regulating cyclin-dependent kinases (CDKs). We here report that paullones also act as very potent inhibitors of glycogen synthase kinase-3β (GSK-3β) (IC50: 4-80 nM) and the neuronal CDK5/p25 (IC50: 20-200 nM). These two enzymes are responsible for most of the hyperphosphorylation of the microtubule-binding protein tau, a feature observed in the brains of patients with Alzheimer's disease and other neurodegenerative 'taupathies'. Alsterpaullone, the most active paullone, was demonstrated to act by competing with ATP for binding to GSK-3β. Alsterpaullone inhibits the phosphorylation of tau in vivo at sites which are typically phosphorylated by GSK-3β in Alzheimer's disease. Alsterpaullone also inhibits the CDK5/p25-dependent phosphorylation of DARPP-32 in mouse striatum slices in vitro. This dual specificity of paullones may turn these compounds into very useful tools for the study and possibly treatment of neurodegenerative and proliferative disorders.
KW - Alzheimer's disease
KW - Cyclin-dependent kinase 5
KW - Glycogen synthase kinase-3
KW - Paullones, kinase inhibitors
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U2 - 10.1046/j.1432-1327.2000.01673.x
DO - 10.1046/j.1432-1327.2000.01673.x
M3 - Article
C2 - 10998059
AN - SCOPUS:0033798031
SN - 0014-2956
VL - 267
SP - 5983
EP - 5994
JO - European Journal of Biochemistry
JF - European Journal of Biochemistry
IS - 19
ER -