ABSTRACT
The importance of the effi cient detection, signaling and activation of cell cycle checkpoints, particularly following the formation of lethal DNA double-strand breaks (DSB) generated either directly for instance following exposure to ionizing radiation (IR) or indirectly during the processing of other DNA adducts or at stalled replication forks, is highlighted by the sensitivity to killing of cells in which the key players of these processes are absent or inhibited. The correct functioning of this DNA damage response (DDR) allows the cell time to repair damage or initiate cell death pathways (Fig. 1). Cancer cells often have defects in components of these damage signaling cascades or in cell cycle control, resulting in a greater dependence on the remaining functional processes. This can potentially be exploited to selectively increase the therapeutic effect of chemo-and radiotherapy in tumour cells by inhibiting the remaining intact DDR pathways and increasing cell death. Over the past decade signifi cant effort has been directed to the development of small molecule inhibitors that target the major kinases involved in these pathways. This review will outline the roles
1Inserm U612, Bats 110-112, Centre Universitaire, Orsay, 91405, France. 2Institut Curie, Bats 110-112, Centre Universitaire, Orsay, 91405, France. aEmail: janet.hall@curie.fr *Corresponding author
of two key phosphoinositide-3 kinase like kinase (PIKK) family members, Ataxia-Telangiectasia mutated (ATM) and ATM and Rad3 related (ATR), which are involved in DNA damage detection and signaling, and of the checkpoint kinases Chk1 and Chk2, which participate in cell cycle control and checkpoint activation in response to DNA damage. We will also discuss the progress made in the discovery and development of selective inhibitors for these four kinases.
