The protein p53 is recognized as one of the most important guardians in the body that prevents tumor development. Since its discovery, the roles of p53 have been the focus of research geared toward understanding the mechanisms of uncontrolled cell growth or cancer. Specifically, when healthy cells are damaged, p53 levels increase, followed by inhibition of cell growth or programmed cell death. This regulation of damaged cells is initiated by a p53-DNA binding event. Mutated forms of p53 that lose the ability to bind DNA can not arrest cell growth, and the proliferation of damaged cells results. Mutant forms of p53 are present in approximately 50% of all human cancers. In other cancers, the overexpression of negative regulators of p53 is present. Over the past 10 years, the phosphatase protein Wip1 has been identified as an over expressed marker of cancer progression, related to suppression of p53 activity. We have created a new class of molecules based on a pyrrole scaffold to inhibit Wip1, and in the past year we have continued to study these small molecules to inhibit the enzymatic activity of Wip1 phosphatase. Our inhibitors show very good selectivity for the Wip1 phosphatase over other similarly related phosphatases. In the past year, we established a cell-based assay to evaluate the activity of these molecules and are testing our molecules. In addition, we have made further improvements to the chemical route to make these molecules and we are developing analogs with good activity.
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