Cyclin-dependent kinase inhibitors: Discovery, development and target rationale for different therapeutic applications

Members of the family of cyclin-dependent kinases (CDKs) fulfill important and partly overlapping roles in the regulation of the cell proliferation cycle and the RNA polymerase-II (RNAP-II) transcription cycle. Clinical development of CDK inhibitors as new anticancer agents has been under way for several years and the first signs of potential efficacy in certain indications have recently been reported. Furthermore, there has been a recent resurgence in the clinical entry of new CDK inhibitors for the treatment of cancer. However, there are numerous other therapeutic applications where inhibition of cell proliferation and transcription with pharmacological CDK inhibitors might be useful. Chief amongst these are proliferative disorders in the areas of nephrology, cardiovascular disease and neurodegeneration. Additionally, infectious diseases in which the invading microorganisms themselves possess CDK-like proteins or depend on the host cell proliferation and transcription machinery are attractive targets. The biomedical rationales for some of these applications of CDK inhibitors are discussed here, with emphasis on the CDK specificity of potential pharmacological agents. Furthermore, progress in the discovery and development of CDK-inhibitory agents is brought up to date.