Small Molecule Activators of p53

p53 小分子激活剂

• 批准号: 7197173
• 负责人: daniel appella
• 金额: --
• 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/7197173
• 关键词: antineoplastics; cell growth regulation; cell line; drug screening /evaluation; gene induction /repression; gene mutation; neoplasm /cancer genetics; neoplastic growth; p53 gene /protein; 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. If mutant p53 can be induced to readopt the active form of wild-type p53, tumor suppressor function can be restored. Molecules that reactivate mutant p53 could selectively target tumor cells due to the accumulation of mutated p53 in these cells. In our research, we are developing a unique class of molecules to reactivate mutant p53 associated with cancer. We have developed a synthetically accessible class of molecules that can be easily modified to examine structural activity relationships, mechanism of biological activity, or optimize for anticancer activity, and we are currently examining the activity of these molecules in a variety of cancer cell lines.

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。如果突变型p53可以被诱导重新选择野生型p53的活性形式，则肿瘤抑制功能可以恢复。重新激活突变型p53的分子可以选择性地靶向肿瘤细胞，因为突变型p53在这些细胞中积累。在我们的研究中，我们正在开发一类独特的分子来重新激活与癌症相关的突变型p53。我们已经开发了一种可合成的分子，可以很容易地进行修饰，以检查结构活性关系，生物活性机制，或优化抗癌活性，我们目前正在研究这些分子在各种癌细胞系中的活性。