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。自发现以来，p53的作用一直是研究的焦点，旨在了解不受控制的细胞生长或癌症的机制。具体来说，当健康细胞受损时，p53水平升高，随后是细胞生长抑制或程序性细胞死亡。这种对受损细胞的调节是由p53-DNA结合事件启动的。失去结合DNA能力的突变形式的p53不能阻止细胞生长，结果是受损细胞的增殖。p53的突变形式存在于大约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，磷酸酶蛋白Wip1已被确定为癌症进展的过度表达标志物，与p53活性的抑制有关。我们已经创建了一类新的基于吡咯支架的分子来抑制Wip1，在过去的一年里，我们继续研究这些小分子来抑制Wip1磷酸酶的酶活性。我们的抑制剂对Wip1磷酸酶的选择性比其他类似的相关磷酸酶好。在过去的一年里，我们建立了一个基于细胞的实验来评估这些分子的活性，并正在测试我们的分子。此外，我们已经进一步改进了化学途径来制造这些分子，我们正在开发具有良好活性的类似物。

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.