Open AccessPaullones are potent inhibitors of glycogen synthase kinase‐3β and cyclin‐dependent kinase 5/p25
Author(s) -
Leost Maryse,
Schultz Christiane,
Link Andreas,
Wu YongZhong,
Biernat Jacek,
Mandelkow EvaMaria,
Bibb James A.,
Snyder Gretchen L.,
Greengard Paul,
Zaharevitz Daniel W.,
Gussio Rick,
Senderowicz Adrian M.,
Sausville Edward A.,
Kunick Conrad,
Meijer Laurent
Publication year - 2000
Publication title -
european journal of biochemistry
Language(s) - English
Resource type - Journals
eISSN - 1432-1033
pISSN - 0014-2956
DOI - 10.1046/j.1432-1327.2000.01673.x
Subject(s) - gsk 3 , cyclin dependent kinase , cyclin dependent kinase 5 , hyperphosphorylation , kinase , glycogen synthase , phosphorylation , gsk3b , biochemistry , chemistry , microbiology and biotechnology , cyclin dependent kinase 2 , biology , protein kinase a , cell cycle , cell
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) (IC 50 : 4–80 n m ) and the neuronal CDK5/p25 (IC 50 : 20–200 n m ). 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.