The search for and potential therapeutic applications of chemical inhibitors of cyclin-dependent kinases

Cyclin-dependent kinases (CDK1, 2, 3, 4, 6, 7) trigger and coordinate the cell division cycle phases. They also play a role in neuronal cells (CDK5) and in the control of transcription (CDK 7, 8, 9). Intensive screening has lead in a few years to the identification of a series of chemical inhibitors of CDKs. Some of these compounds display remarkable selectivities and efficiencies (IC50 < 25 nhl). Many have been co-cristallised with CDK2 and their atomic interactions with the kinase have been analysed in detail: all are located in the ATP-binding pocket of the enzyme. These inhibitors are antimitotic, they arrest cells in GI and, at higher doses, in G2/M. Furthermore they facilitate or even trigger apoptosis in proliferating cells. In contrast, they protect neuronal cells from apoptosis. The potential use of these inhibitors is being extensively evaluated in cancer chemotherapy (clinical trials, phase I and II). Possible clinical applications are being investigated in other fields: cardiovascular (restenosis, tumoral angiogenesis, atherosclerosis), dermatology (psoriasis), nephrology (glomerulonephritis), parasitology (unicellular parasites such as Plasmodium, trypanosomes, toxoplasm, etc.), neurology (Alzheimer's disease), viral infections (cytomegalovirus, HIV, herpes). We anticipate the discovery of novel selective and powerful inhibitors in the near future and hope for their efficient applications in various human pathologies.