Paullones are potent inhibitors of glycogen synthase kinase-3-beta and cyclin-dependent kinase 5/p25 Export

@article{citeulike:2618037, abstract = {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-3beta (GSK-3beta) (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-3beta. Alsterpaullone inhibits the phosphorylation of tau in vivo at sites which are typically phosphorylated by GSK-3beta 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.}, author = {Leost, Maryse and Schultz, Christiane and Link, Andreas and Wu, Yong Z. and Biernat, Jacek and Mandelkow, Eva M. and Bibb, James A. and Snyder, Gretchen L. and Greengard, Paul and Zaharevitz, Daniel W. and Gussio, Rick and Senderowicz, Adrian M. and Sausville, Edward A. and Kunick, Conrad and Meijer, Laurent}, citeulike-article-id = {2618037}, citeulike-linkout-0 = {http://www.blackwell-synergy.com/doi/abs/10.1046/j.1432-1327.2000.01673.x}, citeulike-linkout-1 = {http://dx.doi.org/10.1046/j.1432-1327.2000.01673.x}, doi = {10.1046/j.1432-1327.2000.01673.x}, journal = {European Journal of Biochemistry}, keywords = {akt, b\_catenin, h}, number = {19}, pages = {5983--5994}, posted-at = {2008-04-01 01:35:41}, priority = {2}, title = {Paullones are potent inhibitors of glycogen synthase kinase-3-beta and cyclin-dependent kinase 5/p25}, url = {http://dx.doi.org/10.1046/j.1432-1327.2000.01673.x}, volume = {267}, year = {2000} }

TY - JOUR ID - citeulike:2618037 L3 - citeulike-article-id:2618037 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-3beta (GSK-3beta) (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-3beta. Alsterpaullone inhibits the phosphorylation of tau in vivo at sites which are typically phosphorylated by GSK-3beta 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. IS - 19 JF - European Journal of Biochemistry EP - 5994 TI - Paullones are potent inhibitors of glycogen synthase kinase-3-beta and cyclin-dependent kinase 5/p25 VL - 267 SP - 5983 KW - akt KW - b_catenin KW - h AU - Leost, Maryse AU - Schultz, Christiane AU - Link, Andreas AU - Wu, Yong AU - Biernat, Jacek AU - Mandelkow, Eva AU - Bibb, James AU - Snyder, Gretchen AU - Greengard, Paul AU - Zaharevitz, Daniel AU - Gussio, Rick AU - Senderowicz, Adrian AU - Sausville, Edward AU - Kunick, Conrad AU - Meijer, Laurent PY - 2000/// UR - http://dx.doi.org/10.1046/j.1432-1327.2000.01673.x ER -