CDK inhibitors in 3D: Problems with the drugs, their development plans or their linkage to disease?

Targeting the cell cycle is an attractive anticancer strategy, as its dysregulation is a common, if not ubiquitous, occurrence in tumour development. Cell-cycle control is achieved by the interaction of a complex set of enzymes and other proteins, including the family of protein kinases known as cyclin-dependent kinases (CDKs) and the protein product of the tumour suppressor gene Retinoblastoma. CDKs are required for the orderly progression of cells through the cell cycle and hyperactivation of the CDKs in tumour development, as well as mutation and overexpression of these proteins, is common. Several compounds collectively known as ‘CDK inhibitors’ have been in clinical trials for a number of years. Although often grouped together, they differ in their molecular and cellular modes of action. Several agents in this group, such as flavopiridol, E7070 and UCN-01, have multiple CDK and nonCDK targets or inhibit upstream regulators of the CDKs, whereas other CDK inhibitors, such as CYC-202, appear to target CDK1 and CDK2 more specifically. Most CDK inhibitors are administered intravenously and various schedules have been explored in the clinic. Although generally well tolerated, CDK inhibitors as monotherapy have given mixed efficacy results, possibly due to problems related to specificity or in dosing/scheduling leading to suboptimal exposure. A lack of pharmacodynamic end points, together with the multiple cellular targets of some agents, has made the assessment of ‘CDK inhibition’ and its contribution to antitumour effect in the clinic difficult. However, recent pharmacokinetic studies are examining dosing and scheduling regimens, and novel markers of drug activity and patient suitability are being developed. In addition, newer, specifically targeted oral agents may prove more effective, less toxic and more amenable to optimisation in clinical trials.