Modulating Cell Cycle: Current Applications and Prospects for Future Drug Development

摘要

The cell cycle is a highly conserved and ordered set of events, culminating inncell growth and division. It is tightly controlled by many regulatory mechanisms thatneither permit or restrain its progression. The main families of regulatory proteins thatnplay key roles in controlling cell cycle progression are the cyclins, the cyclin dependentnkinases (Cdks), their substrate proteins, the Cdk inhibitors (CKI) and the tumornsuppressor gene products, p53 and pRb. Many cell cycle control genes, whennderegulated, can cause cells that are not dividing to enter the cell cycle and begin tonproliferate leading to cancer development. They do so by interfacing with the basic cellncycle–regulatory machinery to activate cell cycle entry. There is at present much optimism about thenpossibility of finding anticancer drug treatment strategies that modulate cell cycle regulatory molecules.nCandidate targets for such strategies include crucial cell cycle molecules involved in G1 to S phase or G2 to Mnphase transition. This review will outline the basic regulatory machinery responsible for catalyzing cell cyclenentry and describe the latest advances made in the field of cell cycle regulation. The basis of targeting the cellncycle particularly the Cdks as an approach to developing novel, specific and perhaps more effective anticancerntreatments will be discussed. Examples of novel cell cycle-targeting agents that are in, or are close to being innclinical trials will be provided.