The overall goal of this Project is to examine small molecules synthesized in Project #1 for their ability to disrupt dual specificity phosphatase (DSPase) activity and for their anti-proliferative activity against human solid tumors. This is one of two biochemical components of the Program Project. Our working hypothesis is that the phosphatase activity of some DSPases is responsible for oncogenesis and that selective inhibitors of this activity would generate useful and novel therapeutic agents.
Our Specific Aims are (1) to characterize the in vitro anti-phosphatase activity of all of the novel library compounds, (2) to determine the anti- proliferative effects of the novel library compounds, (3) to assess the anti-phosphatase, anti-proliferative and cell cycle effects of highly active lead compounds and, (4) We will use human breast, prostate and ovarian tumor cells. Moreover, cells with selected temperature sensitive cell cycle control mutations and isogenic cell models, including transformed mouse fibroblasts that over-express Cdc25 DSPases and fibroblasts from mice that lack functional Cdc25A or CDC25B genes, will be incorporated into our assays protocols.
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