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 deveoped a new class of molecules that can accomplish this. Our molecules are based on a non-natural scaffold called peptoids. From our current data, we are redesigning the structure of these molecules to optimize their activity in cellular assays. We are also pursuing the development of small druglike molecules that can selectively kill cells with p53.
| Pokorski, Jonathan K; Jenkins, Lisa M Miller; Feng, Hanqiao et al. (2007) Introduction of a triazole amino acid into a peptoid oligomer induces turn formation in aqueous solution. Org Lett 9:2381-3 |
| Hara, Toshiaki; Durell, Stewart R; Myers, Michael C et al. (2006) Probing the structural requirements of peptoids that inhibit HDM2-p53 interactions. J Am Chem Soc 128:1995-2004 |
| Myers, Michael C; Wang, Jinling; Iera, Jaclyn A et al. (2005) A new family of small molecules to probe the reactivation of mutant p53. J Am Chem Soc 127:6152-3 |
