Melanoma Molecular Maps Projects



Title: List of Chk1 inhibitors
Legend: Molecular machineries, termed checkpoints, tightly regulate progression through the cell cycle. DNA-damaging chemotherapy and radiation activate these functional cellular checkpoints, which facilitate DNA repair by blocking the cell cycle, and promote cell death in case of unrepaired DNA damage. There are at least three DNA damage checkpoints (at G1/S, S, and G2/M) as well as a mitotic spindle checkpoint. Most cancers harbor mutations in tumor suppressors and/or oncogenes, which ultimately leads to checkpoints impairment [1-3]. Inhibiting the remaining cell checkpoints - particularly after exposure of cancer cells to chemotherapy and/or radiation - allows cell death, a strategy now being employed in cancer therapeutics. For instance, the activity of the G1 checkpoint is dependent on the p53 protein. In more than 50% of human tumor cells, the p53 gene is mutated; in melanoma, p53 is rarely mutated, but p53 activity is often compromised due to HDM2 overexpression. In p53 deficient cells, the G1 checkpoint is lacking, and only the G2 checkpoint provides cancer cells with the possibility to repair the DNA after damage. Therefore, combining a G2 checkpoint inhibitor with a DNA damaging agent should selectively force cancer cells into a premature and lethal mitosis, due to an accumulation of DNA lesions. Among the regulators of the G2 checkpoint, Checkpoint 1 kinase (Chk1) plays a major role, which has led to the development of Chk1 inhibitors such as AZD7762, CBP501, CEP-3891, CHIR-124, Isogranulatimide (K00457), PF-00477736, UCN-01 (7-hydroxy staurosporine), and XL844 [1-3]. REFERENCES: [1] Janetka JW et al, Curr Opin Drug Discov Devel 2007, 10:473-86. [2] Bucher N et al, Br J Cancer 2008, 98:523-8.
Author: The MMMP Team (updated: Feb 2008)

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