Small Molecule Activators of p53

P53蛋白被认为是体内防止肿瘤发展的最重要的守护者之一。自从它被发现以来，p53的作用一直是旨在了解细胞生长失控或癌症机制的研究的重点。具体地说，当健康细胞受损时，P53水平会增加，随后细胞生长受到抑制或细胞程序性死亡。这种对受损细胞的调节是由P53-DNA结合事件启动的。丧失结合DNA能力的突变形式的p53不能阻止细胞生长，并导致受损细胞的增殖。突变型p53存在于大约50%的人类癌症中。在其他癌症中，存在P53负调控因子的过度表达。在过去的10年里，Hdm2蛋白被认为是癌症中存在的这些过度表达的负调控因子之一。能够抑制Hdm2-P53复合体形成的分子可以恢复癌症中正常的P53功能。我们已经创造了一类新的基于N-酰基多胺(Napas)的分子作为Hdm2的合成抑制剂。这些分子还以密切相关的蛋白质HDMX为靶标，HDMX正在成为同样重要的靶标。在过去的一年里，我们已经开始开发一类新的小分子来抑制Wip1磷酸酶的活性，Wip1磷酸酶是P53功能的重要调节因子。我们的抑制剂对Wip1磷酸酶表现出非常好的选择性，而不是其他类似的相关磷酸酶，我们目前正在基于细胞的分析中探索它们的活性。此外，我们还完成了对另一种名为邦52的小分子的研究。这种分子通过促进一种名为bclxl的蛋白质的降解来独特地诱导细胞凋亡。我们正在继续研究这种分子的机制，并确定一个目标。

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 initiated development of 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 completed a study of another small molecule that we call Bang52. This molecule uniquely induces apoptosis in cells by promoting degradation of a protein called bcl-xl. We are continuing to study the mechanism of this molecule and identify a target.