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 protein HDM2 has been recognized as one of these overexpressed negative regulators that is present in cancers. Molecules that can inhibit formation of an HDM2-p53 complex can restore normal p53 function in cancer. We have created a new class of molecules based on N-acylated polyamines (NAPAs) as synthetic inhibitors of HDM2. These molecules also target the closely-related protein HDMX, which is emerging as an equally important target. The past year we have continued to study a new class of small molecules to inhibit the activity of Wip1 phosphatase, and important regulator of p53 function. Our inhibitors show very good selectivity for the Wip1 phosphatase over other similarly related phosphatases, and we are currently exploring their activity in cell-based assays. In addition, we have improved the chemical route to make these inhibitors and we are exploring activities of derivatives.
