Novel Checkpoint 1 Inhibitors
Affiliation: Laboratoire SEESIB,Universite Blaise Pascal, UMR 6504 du CNRS, 63177 Aubiere, France.
Keywords: G2 checkpoint, Chk1 inhibitors, anticancer agents, cell cycle, benzimidazole quinolines, diazepinoindole derivatives, diarylurea derivatives, aminopyrazoles
Cell cycle ckeckpoints are activated in response to DNA damage. Their role consists in blocking the cell cycle to allow time for DNA repair. 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 the p53 mutated cells, the G1 checkpoint is lacking. In these cells, only the G2 checkpoint, although weaker than in healthy cells, provides cancer cells with the opportunity to repair the DNA after damage. Therefore, combining a G2 checkpoint inhibitor with a DNA damaging agent should force, selectively 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. A widespread interest has been recently devoted to the discovery of Chk1 inhibitors as potential useful compounds to enhance the antitumor efficiency of DNA damaging agents. This review article will summarize: (i) the chemical structures of the novel Chk1 inhibitors reported in the recent patents; (ii) their inhibitory activity towards Chk1; (iii) their effects on tumor cells in combination with DNA damaging agents; and (iv) the in vivo results on animal models.
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