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。如果能诱导突变型P53重新选择野生型P53的活性形式，肿瘤抑制功能就可以恢复。重新激活突变的p53的分子可以选择性地靶向肿瘤细胞，因为突变的p53在这些细胞中积累。在我们的研究中，我们正在开发一种独特的分子来重新激活与癌症相关的突变的p53。我们已经开发了一类可合成的分子，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，目前我们正在检测这些分子在各种癌细胞系中的活性。

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.