Small Molecule Activators of p53

蛋白质p53被认为是体内防止肿瘤发展的最重要的监护人之一。自发现以来，p53的作用一直是研究的重点，旨在了解不受控制的细胞生长或癌症的机制。 具体而言，当健康细胞受损时，p53水平增加，随后细胞生长受到抑制或程序性细胞死亡。受损细胞的这种调节是由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，并且导致受损细胞的增殖。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负调节因子的过度表达。 在过去的10年中，磷酸酶蛋白Wip 1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。 我们正在开发一类新的分子来抑制Wip 1，在过去的一年里，我们继续研究这些小分子来抑制Wip 1磷酸酶的酶活性。 我们的抑制剂对Wip 1磷酸酶显示出非常好的选择性，优于其他类似相关的磷酸酶。 在过去的一年里，我们继续制造更多的分子类似物，以提高生物活性。此外，我们还进一步改进了制造这些分子的化学路线。 我们希望找到具有良好生物活性的类似物，这些类似物可以转化为癌症的动物模型，并最终作为人类的新疗法向前发展。

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.