ABSTRACT
Abnormal phosphorylation of cellular proteins is frequently observed in human disease. For this reason, there has been a growing interest in the discovery and optimization of protein kinase inhibitors (review in Cohen, 2002). Indeed, after G-protein-coupled receptors, protein kinases constitute the second class of drug discovery screening targets. Fifty-five kinase inhibitors are currently undergoing clinical evaluation against various human diseases. Some, such as imatinib (Gleevec) or gefitinib (Iressa), have actually achieved real market success and have provided proof-of-principle that small molecule kinase inhibitors can be effective drugs. Among the human 518
+
kinases, cyclin-dependent kinases (CDKs) regulate the cell
(34-40 kDa) that are inactive in a monomeric state. To be active, they require an association with one of the cyclins, their regulatory subunits. Frequent deregulation of CDKs in cancers, neurodegenerative diseases, and other pathologies justify the active search for chemical inhibitors able to reversibly and selectively inhibit this class of enzymes. Intensive screening of collections of natural and synthetic compounds has led to the identification of several families of CDK inhibitors, most of which act by competition with ATP for binding at the catalytic site. Although the therapeutic potential of the most promising compounds is currently being evaluated in preclinical and clinical trials, their exact mechanism of action and the real spectrum of their intracellular targets remain largely unknown. Determination of the
in vivo
selectivity of the compounds and identification of their intracellular targets constitute a prerequisite to understand their cellular effects and to improve their efficiency on a rational basis.
