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，HDM2蛋白被认为是癌症中过度表达的负调控因子之一。抑制HDM2-p53复合体形成的分子可以在癌症中恢复正常的p53功能。我们已经开发出一种新的分子来实现这一目标。我们的分子是基于一种叫做类肽的非天然支架。根据我们目前的数据，我们正在重新设计这些分子的结构，以优化它们在细胞分析中的活性。我们也在开发类似药物的小分子，可以选择性地杀死带有p53的细胞。

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.