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Selective Cyclin-dependent Kinase 2/Cyclin A Antagonists that Differ from ATP Site Inhibitors Block Tumor Growth

Departments of Molecular Oncology [N. M., S. F., R. S., D. W.], Bioorganic Chemistry [J. M.], and Pathology [H. K.], Genentech, Inc., South San Francisco, California 94080

A central function of the tumor suppressor retinoblastoma (Rb) is its ability to repress E2F transcriptional activity. Many cancers harbor inactivated Rb and consequently deregulated E2F. RXL peptides inhibit E2F recruitment and phosphorylation by CDK2/cyclin A. Here we report that RXL peptides selectively kill tumor cells with deregulated Rb/cyclin D pathways. We extend these observations to tumor models and demonstrate inhibition of tumor growth in SV40 large T transformed Balb/c 3T3 grafts and in HER2 transgenic tumors. Moreover, our observations reveal that RXL peptide-treated tumors undergo apoptosis. Our results indicate that RXL motif-based inhibitors will provide selective antiproliferative agents with in vivo efficacy in tumors with deregulated Rb/cyclin D pathways.

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