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Characterization of a Novel Cyclin-Dependent Kinase 1 Inhibitor, BMI-1026^{1 ,2}

Laboratory of Metabolism [Y-S. S., S-Y. K., K. S. L.] and Laboratory of Cellular Carcinogenesis and Tumor Promotion [L. L., S. H. Y.], Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892; LG Biomedical Institute, La Jolla, California 92037 [C. M., J. Y. Y., X. C., K. K., H-H. C.]

Cyclin-dependent kinases (Cdks) have been attractive targets for the development of anticancer therapeutic agents. In an effort to generate a new class of anti-Cdk inhibitors, we synthesized aryl aminopyrimidines and examined the effect of these compounds in both in vitro kinase assays and cultured cells. Two of these compounds, BMI-1026 and BMI-1042, induced a strong cell cycle alteration with potent inhibitory activities against cyclin-dependent kinases, collectively known as Cdks. Characterization of BMI-1026 revealed that it imposes a potent G₂-M arrest and mild G₁-S and S arrests. In vitro biochemical analyses and in vivo time-lapse microscopy studies revealed that it induces a mitotic catastrophe and precocious mitotic exit even in the presence of nocodazole. These defects appeared to lead to apoptotic cell death in tumorigenic cell lines. Consistent with the induction of mitotic defects and apoptosis, BMI-1026 imposed a selective sensitivity to proliferating versus differentiating or growth-arrested mouse keratinocytes. These data suggest that BMI-1026 could be developed as a potential anti-Cdk1 chemotherapeutic agent.

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