Small Molecule Activators of p53

p53 小分子激活剂

• 批准号: 7593520
• 负责人: daniel appella
• 金额: $ 29.29万
• 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/7593520
• 关键词: Adverse effects; Apoptosis; Cancerous; Cells; Cellular Assay; Class; Complex; DNA Binding; Data; Development; Event; Human; MDM2 gene; Malignant Neoplasms; Mutate; Pathway interactions; Patients; Peptoids; Protein Overexpression; Protein p53; Proteins; Regulation; Research; Role; Structure; TP53 gene; base; cancer therapy; cell growth; cell injury; cell killing; cellular targeting; chemotherapy; design; mutant; 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 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.

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。自从它被发现以来，p53的作用一直是旨在了解细胞生长失控或癌症机制的研究的重点。具体地说，当健康细胞受损时，P53水平会增加，随后细胞生长受到抑制或细胞程序性死亡。这种对受损细胞的调节是由P53-DNA结合事件启动的。丧失结合DNA能力的突变形式的p53不能阻止细胞生长，并导致受损细胞的增殖。突变型p53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存在的这些过度表达的负调控因子之一。能够抑制Hdm2-P53复合体形成的分子可以恢复癌症中正常的P53功能。我们已经开发出一类新的分子来实现这一点。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，以优化它们在细胞检测中的活性。我们还在开发能够选择性地杀死带有p53的细胞的小的类似药物的分子。