Paullones are potent inhibitors of glycogen synthase kinase‐3β and cyclin‐dependent kinase 5/p25

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-3b (GSK-3b) (IC 50 : 4±80 nm) and the neuronal CDK5/p25 (IC 50 : 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-3b. Alsterpaullone inhibits the phosphorylation of tau in vivo at sites which are typically phosphorylated by GSK-3b 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.Keywords: Alzheimer's disease; cyclin-dependent kinase 5; glycogen synthase kinase-3; paullones, kinase inhibitors.Phosphorylation on serine, threonine and tyrosine residues by protein kinases constitute one of most common mechanisms of post-translational modifications of proteins. Among the estimated 2000 human protein kinases, we are presently investigating the functions of two related families of kinases, the cyclin-dependent kinases (CDKs) and glycogen synthase kinases 3 (GSK-3) [1,2] (see also http://www.sdsc.edu/kinases). CDKs play a key role in cell cycle regulation, centrosome duplication, transcription, muscular and neural functions and apoptosis (reviewed in [3±8]). GSK-3 is involved in the WNT signaling pathway [9], cell cycle regulation [10,11]

Development of an Assay to Screen for Inhibitors of Tau Phosphorylation by Cdk5

“…40 Alsterpaullone, a selective inhibitor for cdk5 and glycogen synthase kinase, inhibits the in vivo phosphorylation of tau at AD-specific sites in slices from mouse striatum. 31 Some of the inhibitors have been co-crystallized with cdk2. Most of the potent inhibitors mentioned above are competitive inhibitors for the ATP binding site in cdk5.…”

Intracellular Targets of Paullones

“…A structure/activity relationship study has led to the more active compounds kenpaullone and alsterpaullone (11). During a classical selectivity study, we found that paullones were also excellent GSK-3 inhibitors (13). Kenpaullone and alsterpaullone are about 10-fold more potent at inhibiting GSK-3 compared with CDK1 (13).…”

“…14 -20). GSK-3 inhibitors include indirubins (10), paullones (13), maleimides (21,22), and lithium (23).…”

“…During a classical selectivity study, we found that paullones were also excellent GSK-3 inhibitors (13). Kenpaullone and alsterpaullone are about 10-fold more potent at inhibiting GSK-3 compared with CDK1 (13). Nevertheless, the true selectivity of paullones needs to be defined.…”

Planejamento racional de candidatos a fármacos inibidores de glicogênio sintase cinase - 3 beta (GSK-3B) em doença de Alzheimer

“…Vários grupos de pesquisa têm identificado alternativamente pequenas moléculas como sendo potenciais inibidores da GSK-3 (HERS; TAVARE; DENTON, 1999;COGHLAN et al, 2000;MEIJER et al, 2000;LECLERC et al, 2001;MARTINEZ et al, 2002). Himenialdisina (IC50 = 10 nM) (MEIJER et al, O grupo ribose da AMP-PNP interage com a GSK-3β através de uma única ligação de hidrogênio com Gln185.…”