Small Molecule Activators of p53

p53 小分子激活剂

• 批准号: 8741394
• 负责人: DANIEL H APPELLA
• 金额: $ 13.72万
• 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/8741394
• 关键词: Adverse effects; Apoptosis; Biological Assay; Cancerous; Cells; Chemicals; DNA Binding; Development; Event; Human; Malignant Neoplasms; Mutate; Pathway interactions; Patients; Phosphoric Monoester Hydrolases; Protein p53; Protein phosphatase; Proteins; Pyrroles; Regulation; Research; Role; Route; Testing; analog; base; cancer therapy; cell growth; cell injury; cellular targeting; chemotherapy; design; inhibitor/antagonist; mutant; overexpression; prevent; scaffold; small molecule; tumor; tumor progression; uncontrolled cell growth

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.

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。 我们已经创建了一类基于吡咯支架的新分子来抑制Wip 1，在过去的一年中，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，我们建立了一种基于细胞的检测方法来评估这些分子的活性，并正在测试我们的分子。此外，我们还对制造这些分子的化学途径进行了进一步的改进，我们正在开发具有良好活性的类似物。