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An Indolocarbazole Inhibitor of Human Checkpoint Kinase (Chk1) Abrogates Cell Cycle Arrest Caused by DNA Damage

Departments of Oncology [J. R. J., A. G., J. D. W.] and Immunology [C. I., L. A. M., A. R.], SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406

Many cancer therapies cause DNA damage to effectively kill proliferating tumor cells; however, a major limitation of current therapies is the emergence of resistant tumors following initial treatment. Cell cycle checkpoints are involved in the response to DNA damage and specifically prevent cell cycle progression to allow DNA repair. Tumor cells can take advantage of the G₂ checkpoint to arrest following DNA damage and avoid immediate cell death. This can contribute to acquisition of drug resistance. By abrogating the G₂ checkpoint arrest, it may be possible to synergistically augment tumor cell death induced by DNA damage and circumvent resistance. This requires an understanding of the molecules involved in regulating the checkpoints. Human Chk1 is a recently identified homologue of the Schizosaccharomyces pombe checkpoint kinase gene, which is required for G₂ arrest in response to DNA damage. Chk1 phosphorylates the dual specificity phosphatase cdc25C on Ser-216, and this may be involved in preventing cdc25 from activating cdc2/cyclinB and initiating mitosis. To further study the role of Chk1 in G₂ checkpoint control, we identified a potent and selective indolocarbazole inhibitor (SB-218078) of Chk1 kinase activity and used this compound to assess cell cycle checkpoint responses. Limited DNA damage induced by -irradiation or the topoisomerase I inhibitor topotecan was used to induce G₂ arrest in HeLa cells. In the presence of the Chk1 inhibitor, the cells did not arrest following -irradiation or treatment with topotecan, but continued into mitosis. Abrogation of the damage-arrest checkpoint also enhanced the cytotoxicity of topoisomerase I inhibitors. These studies suggest that Chk1 activity is required for G₂ arrest following DNA damage.

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