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A Novel cdk2-selective Inhibitor, SU9516, Induces Apoptosis in Colon Carcinoma Cells¹

Division of Oncology, Department of Medicine, Albert Einstein College of Medicine and the Albert Einstein Cancer Center, Bronx, New York 10461 [M. E. L., B. Y., R. G. P., S. W.], and SUGEN, South San Francisco, California 94080 [A. R., K. E. L., C. L., L. S., C. T., G. M.]

Recent studies have indicated that the development of cyclin-dependent kinase (cdk)2 inhibitors that deregulate E2F are a plausible pharmacological strategy for novel antineoplastic agents. We show here that 3-[1-(3H-Imidazol-4-yl)-meth-(Z)-ylidene]-5-methoxy-1,3-dihydro-indol-2-one (SU9516), a novel 3-substituted indolinone compound, binds to and selectively inhibits the activity of cdk2. This inhibition results in a time-dependent decrease (4–64%) in the phosphorylation of the retinoblastoma protein pRb, an increase in caspase-3 activation (5–84%), and alterations in cell cycle resulting in either a G₀-G₁ or a G₂-M block. We also report here cell line differences in the cdk-dependent phosphorylation of pRb. These findings demonstrate that SU9516 is a selective cdk2 inhibitor and support the theory that compounds that inhibit cdk2 are viable resources in the development of new antineoplastic agents.

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