Chemical inhibitors of cyclin-dependent kinases: preclinical and clinical studies.

the past decade, the use of a large variety of cellular models and cell bio logy, biochemistry and molecular biology techniques has led to the discover y of key proteins that are intimately involved in the regulation of tumor g rowth. In particular it has been shown that cyclin-dependent kinases (CDKs) are key regulators of the cell-division cycle. Their frequent deregulation in human tumors make them attractive targets for the identification of new antineoplasic agents. Intensive screening has led in the past few years to the identification of a series of selective and potent chemical inhibitors of CDKs. Drugs representing new lead structures like flavopiridol, indirub in and staurosporine derivatives have already been used in clinical evaluat ion for cancer treatment (clinical trials, phase I and II). Anticancer drug development is being pursued to reduce their toxic side effects, to improv e their pharmacokinetic properties and to increase their anti-tumor activit y. In this context, traditional drug screening methods in biological test s ystems have led to the discovery of new compounds such as purine derivative s and paullones, which display remarkable selectivity and efficiency. These novels drugs may result in substantial progress in cancer treatment in the near future. (C) 2000 Editions scientifiques et medicales Elsevier SAS.