Full Project 2: Synthesis and MAPK Kinase Inhibitiory Activities in Vitro and In

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Prostate cancer is the most commonly diagnosed cancer in American men. In 2005, an estimated 230,900 new cases will be diagnosed. Although androgen ablation is highly effective palliative therapy, all men eventually relapse due to the presence of androgen independent prostate cancer cells within metastatic sites. Currently there is no therapy that effectively eliminates these androgen independent prostate cancer cells. Identification of the signal transduction pathways responsible for survival and proliferation of androgen independent prostate cancer cells is critical for rational drug development. In preliminary studies, imido-substituted 2-chloro-1,4-naphthoquinones have been identified, that are selective inhibitors of Mek-1. Over the past year approximately 75 napthoquinone analogs have been synthesized and tested for cytotoxicity against a panel of human prostate cancer cell lines. These studies have identified certain structure-cytotoxicity relationships that will be exploited in synthesis of additional analogs. The goal of the studies is to identify potent cytotoxic imido-substituted napthoquinones that will be analyzed for inhibitory activity against MEK-1 and other membrane bound and intracellular protein kinases.