Cyclin‐dependent kinases (cdk) play an essential role in the intracellular control of the cell division cycle (cdc). These kinases and their regulators are frequently deregulated in human tumours. Enzymatic screening has recently led to the discovery of specific inhibitors of cyclin‐dependent kinases, such as butyrolactone I, flavopiridol and the purine olomoucine. Among a series of C2, N⁶, N9‐substituted ade‐nines tested on purified cdc2/cylin B, 2‐(1‐ethyl‐2‐hydroxyethylamino)‐6‐benzylamino‐9‐isopropylpu‐rine (roscovitine) displays high efficiency and high selectivity towards some cyclin‐dependent kinases. The kinase specificity of roscovitine was investigated with 25 highly purified kinases (including protein kinase A, G and C isoforms, myosin light‐chain kinase, casein kinase 2, insulin receptor tyrosine kinase, c‐src, v‐abl). Most kinases are not significantly inhibited by roscovitine. cdc2/cyclin B, cdk2/cyclin A, cdk2/cyclin E and cdkSlp35 only are substantially inhibited (IC₅₀values of 0.65, 0.7, 0.7 and 0.2 μM, respectively). cdk4/cyclin D1 and cdk6/cyclin D2 are very poorly inhibited by roscovitine (IC₅₀>100 μM). Extracellular regulated kinases erkl and erk2 are inhibited with an IC₅₀of 34 μM and 14 μM, respectively. Roscovitine reversibly arrests starfish oocytes and sea urchin embryos in late pro‐phase. Roscovitine inhibitsin vitroM‐phase‐promoting factor activity andin vitroDNA synthesis inXenopusegg extracts. It blocks progesterone‐induced oocyte maturation ofXenopusoocytes andin vivophosphorylation of the elongation factor eEF‐1. Roscovitine inhibits the proliferation of mammalian cell lines with an average IC₅₀] of 16 μM. In the presence of roscovitine L1210 cells arrest in G1 and accumulate in G2.In vivophosphorylation of vimentin on Ser55 by cdc2/cyclin B is inhibited by roscovitine. Through its unique selectivity for some cyclin‐dependent kinases, roscovitine provides a useful anti‐mitotic reagent for cell cycle studies and may prove interesting to control cells with deregulated cdc2, cdk2 or cdk5 kinase activities.

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.