Small Molecule Activators of p53

p53 小分子激活剂

• 批准号: 8148726
• 负责人: DANIEL H APPELLA
• 金额: $ 38.96万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8148726
• 关键词: DNA Binding; TP53 gene; prevent; small molecule

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.

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。我们创造了一类基于n -酰基化多胺（NAPAs）的新分子作为HDM2的合成抑制剂。这些分子也针对密切相关的HDMX蛋白，这是一个同样重要的目标。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磷酸酶的选择性比其他类似的相关磷酸酶高，我们目前正在基于细胞的实验中探索它们的活性。此外，我们还完成了另一种小分子的研究，我们称之为Bang52。这种分子通过促进一种叫做bcl-xl的蛋白质的降解而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。