Characterization of Novel Inhibitors of Cyclin-Dependent Kinases

In epithelial cells progression through the G1 phase of the cell cycle and preparing the cell for the S phase is regulated by cyclin D1-cdk4. Cells that express the retinoblastoma protein (pRb) are dependent on cyclin D1-cdk4 activity for their proliferation while cells that do not express pRb are not. Overexpression of cyclin D1 and/or cdk4, and loss of expression of p16 (the natural inhibitor of cyclin D1-cdk4 activity), have been implicated in several cancers. These data suggest that the aberrant activity of cyclin D1-cdk4 correlates with the tumor phenotype. Hence, blocking cyclin D1-cdk4 activity may prove to be an effective anticancer therapy for pRb+ tumors. In this paper, we report the identification of four novel compounds that selectively inhibit cyclin D1-cdk4 activity to various degrees. We further demonstrate that two of these compounds also selectively inhibit the target, pRb+ tumor cells. The implications of these discoveries and their utility as anticancer agents are discussed.