ABSTRACT
One of the most important part in the cellular response to DNA damage is the activation of Chk, Checkpoint kinase (Chk1 and Chk2) phosphorylation are a key enzyme to obtain cell-cycle arrests. Chks inhibition is believed to sensitize the tumor cells to cancer drugs that damage the DNA, because of the absence of both efficient DNA repair and checkpoints, the cell death or senescence will occur. There are several rationales for the development of Chk inhibitors. First, a wide range of anticancer drugs and ionizing radiation (IR) caused activation of Chk in tumor cells which seriously limited their effectiveness in these cancer cells. These shortcomings of current chemotherapeutic approaches can be addressed by selective inhibition of Chk. Second, inhibition of Chk in normal cells leads to protection of the normal tissues during chemotherapy or radiation therapy that increase the therapeutic index of DNA-targeted and IR agents in these cells. Therefore, Chk inhibitors would protect healthy tissues as well as sensitize the tumor to chemotherapy and IR. Hence, the Chks have been identified as promising targets for anticancer drug design. This chapter will describe and discuss in more detail the most recent inhibitors of Chk1 and Chk2, as reported in the literature including an evaluation of chemical structure and biological activity.
