Cell cycle inhibitors for the treatment of cancer

The loss of cell cycle control leading to deregulated cell proliferation is one of the hallmarks of cancer. The cell cycle progression is regulated by the activities of cydin-dependent kinases (CDKs) and their subunits known as cyclins. Cell cycle regulators are often mutated in human neoplasia, resulting in outcomes such as overexpression of CDKs and cyclins, as well as loss of natural inhibitors of CDKs, and consequently hyperactivation of CDKs. Inhibition of CDKs thus provides an attractive therapeutic strategy for the treatment of cancer. Over the past few years, many small-molecule CDK inhibitors have been discovered and at least 4 have entered into clinical trials. These include both pan CDK inhibitors such as flavopiridio and UCN-01, along with the more selective CDK2 inhibitors, (R)-roscovitine and BMS-387042. On the other hand, the transition from one phase of the cell cycle to the next is controlled by cell cycle checkpoiunts and may represent a viable alternative target for cell cycle modulation. The recent understanding of the critical role of checkpoint kinase 1 (Chk1) in the G 2 checkpoint has generated great interest in the discovery of Chk1 inhibitors. This review discusses the progress of preclinical research and clinical developments of CDK inhibitors and the recently disclosed Chk1 inhibitors.