Chapter 2 - Novel targets in the cell cycle and cell cycle checkpoints

Abstract

The chapter focuses on cell cycle and checkpoint control, discusses the rationale for targeting these pathways, and reviews the pharmacology of the agents that are currently known to act on the cell cycle control and checkpoint pathways. Cell cycle checkpoints are mechanisms that monitor cell regulatory pathways and DNA structure before the cells enter the next phase of the cell cycle. Their activation in response to DNA damage either leads to cell cycle arrest to allow repair of DNA damage, or leads to cell death by apoptosis or terminal growth arrest. Alterations of the cell cycle control and checkpoint pathways are generally present in human cancers and such deficiencies can be identified in patient tumors. The dependence of tumors on activated cyclin-dependent kinases and the apparent deficiencies of tumor cells with respect to redundant pathways provide a rationale for the use of cyclin-dependent kinase inhibitors as anticancer agents. The key proteins in these pathways have been identified, and these can be used to study the interactions of drugs at the molecular level and for the discovery of novel inhibitors. Various small molecule inhibitors have also been discovered, some of which are in early clinical trials. Gene therapy has also been applied successfully for p53. An important challenge is to integrate the cell cycle and checkpoint pathways in a logical and comprehensive framework, to increase the selectivity of current therapies against specific targets, and to adapt these therapies to individual patients based on the molecular dissection of their tumors.