The identification of paullones as a family of CDK inhibitors has been followed by several unexpected findings, specifically their stronger affinity for GSK-3, and their interactions with mitochondrial MDH. This, in fact, has opened the way to alternative applications beyond the initial anti-cancer application (Zaharevitz et al. 1999), which had not been initially predicted, namely the use against neurodegenerative disorders. As CDK/GSK-3 dual specificity inhibitors, paullones could be highly advantageous, since both CDK5/p25 (Cruz et al. 2003; Noble et al. 2003) and GSK-3 (Caricasole 2003; De Strooper and Woodgett 2003; Phiel et al. 2003) have been shown to play essential roles in the development of Alzheimer's disease. CDK5 has also been shown to mediate dopaminergic neuron loss in Parkinson's disease (Smith et al. 2003). Recently modulation of N-methyl-d-aspartate receptors by CDK5 has been shown to represent a primary event underlying the ischaemic injury of CA1 pyramidal neurons as observed in stroke (Wang et al. 2003). Therefore CDK inhibitors like paullones may have an input in the treatment of Parkinson's disease and stroke as well. Finally, as GSK-3-selective drugs, paullones may find applications in the treatment of diabetes type 2 and as a tool to maintain undifferentiated embryonic stem cells (Sato et al. 2004).
Acknowledgements This research was supported by the "Association pour la Recherche sur le Cancer" (L.M.) and the Ministère de la Recherche/INSERM/CNRS "Molécules et Cibles Thérapeutiques" Programme. This review was written during a sabbatical leave at Rockefeller University, in the laboratory of Paul Greengard, who is warmly acknowledged. Supported by CNRS, Rockefeller University and NATO.
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