Roscovitine and other purines as kinase inhibitors. From starfish oocytes to clinical trials

Abstract

This article reviews the steps that have led us from very fundamental research on the cell division cycle, investigated with the starfish oocyte model, to the identification of drugs now being evaluated against cancer in the clinic. Among protein kinases activated during entry in M phase, the cyclin-dependent kinase CDK1/cyclin B was initially identified as a universal M-phase promoting factor. It was then used as a screening target to identify pharmacological inhibitors. The first inhibitors to be discovered were 6-dimethylaminopurine and isopentenyladenine, from which more potent and selective inhibitors were optimized (olomoucine, roscovitine, and purvalanols). All were cocrystallized with CDK2 and found to localize in the ATP-binding pocket of the kinase. Their selectivity and cellular effects have been thoroughly investigated. Following encouraging results obtained in preclinical tests and favorable pharmacological properties, one of these purines, roscovitine (CYC202), is now entering phase II clinical trials against cancers and phase I clinical tests against glomerulonephritis. CDK inhibitors are also being evaluated, at the preclinical level, for therapeutic use against neurodegenerative diseases, cardiovascular disorders, viral infections, and parasitic protozoa. This initially unexpected scope of potential applications and the large number and chemical diversity of pharmacological inhibitors of CDKs now available constitute a very encouraging stimulus to pursue the search for optimization and characterization of protein kinase inhibitors, from which we expect numerous therapeutic applications.