Fig. 4
From: The cell cycle checkpoint inhibitors in the treatment of leukemias
Schematic representation of the mechanism of action of CHK1/CHK2 inhibitor. In both normal and tumor cells, the recognition of damages on DNA by the DDR-sensors activates different cell cycle checkpoints. The central event of checkpoint activation is the inhibition of the phosphatases CDC25s which is necessary for the activation of the complexes CDK-cyclins. Both ATR/CHK1 and ATM/CHK2 pathways promote CDC25s inhibition (ubiquitin-dependent degradation) and, consequently, they arrest cell cycle in response to DNA damages. Tumor cells can activate these pathways in response to DNA damaging agents and survive. The treatment with a CHK1/CHK2 inhibitor avoids the degradation of the phosphatase CDC25s, inducing cell cycle progression even in the presence of DNA damages. For this reason, different CHK1/CHK2 inhibitors have been developed to enhance the DNA damaging from chemotherapeutic drugs by inhibiting the cell cycle checkpoint negative signals