ATP-site directed inhibitors of cyclin-dependent kinases

Cyclin-dependent kinases trigger and coordinate transitions between differe nt phases the cell division cycle (CDK1, 2, 3, 4, 6, 7). They also play a r ole in apoptosis (CDK2), in neuronal cells (CDK5) and in the control of tra nscription (CDK 7, 8, 9). Intensive screening has lead to the recent identi fication of a series of chemical inhibitors of CDKs: olomoucine, roscovitin e, purvalanol, CVT-313, flavopiridol, gamma-butyrolactone, indirubins, paul lones and staurosporine. Some of these compounds display remarkable selecti vities and efficiencies (IC50 < 25 nM). Many have been co-crystallised with CDK2 and their interactions with the kinase have been analysed in atomic d etail. These inhibitors all act by competing with ATP for binding at the ca talytic site. Most inhibitors present a flat heterocyclic ring system that occupies the purine binding pocket as well as form 2 or 3 hydrogen bonds wi th Glu-81 and Leu-83. The binding modes of these inhibitors are reviewed in this article. Knowledge of the CDK/inhibitor interactions will be of great help to design inhibitors with improved selectivity our potency as well as to generate affinity chromatography matrices for the purification and iden tification of their cellular targets. The potential use of CDK inhibitors i s being extensively evaluated in cancer chemotherapy and other fields such as the cardiovascular domain (restenosis), dermatology (psoriasis), nephrol ogy (glomerulonephritis) parasitology (unicellular parasites such as Plasmo dium, Trypanosomes, Toxoplasm,...etc.), neurology (Alzheimer's disease) and viral infections (cytomegalovirus, H.I.V., herpes).