Our goal is to develop a drug that inhibits the oncogene WIP1 (PPM1D). We previously determined that WlP1 is amplified at the DNA level in breast tumors and is overexpressed at the RNA level in breast and metastatic prostate tumors [10]. Additional studies have shown that WlP1 overexpression promotes cell proliferation and protects cells from apoptosis, properties consistent with a role in cancer [3, 6, 10, 17]. We have completed a high-throughput screen which identified compounds that inhibit Wip1 phosphatase activity in vitro. In this grant we propose to use these inhibitory compounds to generate leads for creating a Wip1-specific anti-cancer drug. First, the inhibitors will be biochemically characterized to rank their potency, to determine specificity for Wip1 compared to other phosphatases, and to investigate the mechanism of enzyme inhibition. Second, assays will be developed for testing the ability of these compounds to inhibit Wip1 function in cultured cells. Third, medicinal chemistry will be initiated to develop compounds that have increased potency, specificity, and cell-based activity. Finally, these compounds, including those obtained from medicinal chemistry, will be tested for their ability to inhibit tumor formation in mice. Assuming all of these efforts are successful, this work will result in a pre-clinical candidate for a novel anti-cancer drug.
