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 are developing a new class of molecules 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 are continuing to make more analogs of our molecules to improve the biological activity. In addition, we have made further improvements to the chemical route to make these molecules. We hope to find analogs with good biological activity that may be translated into animal models for cancer, and eventually moved forward as new treatments for people.
