A novel cdk2-selective inhibitor, SU9516, induces apoptosis in colon carcinoma cells

Recent studies have indicated that the development of cyclin-dependent kina se (cdk)2 inhibitors that deregulate E2F are a plausible pharmacological st rategy 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 nove l 3-substituted indolinone compound, binds to and selectively inhibits the activity of cdk2. This inhibition results in a time-dependent decrease (4-6 4%) in the phosphorylation of the retinoblastoma protein pRb, an increase i n caspase-3 activation (5-84%), and alterations in cell cycle resulting in either a G(0)-G(1) or a G-NI block. We also report here cell line differenc es in the cdk-dependent phosphorylation of pRb. These findings demonstrate that SU9516 is a selective cdk2 inhibitor and support the theory that compo unds Thai inhibit cdk2 are viable resources in the development of new antin eoplastic agents.