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，蛋白质HDM 2已被认为是存在于癌症中的这些过度表达的负调节因子之一。可以抑制HDM 2-p53复合物形成的分子可以恢复癌症中正常的p53功能。在过去的一年里，我们已经开发了一类新的分子，可以实现这一点。我们正在继续优化这些分子的活性，并探索它们在细胞测定中的活性。

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. Over the past year, we have deveoped a new class of molecules that can accomplish this. We are continuing to optimize the activity of these molecules, and explore their activity in cellular assays.