文章：

唤醒守护天使：给p53通路用药

Awakening guardian angels: drugging the p53 pathway

原文发布日期：2009-12-01

DOI: 10.1038/nrc2763

类型: Review Article

开放获取: 否

要点：

1. p53 functions as the 'guardian of the genome' by inducing cell cycle arrest, senescence and apoptosis in response to oncogene activation, DNA damage and other stress signals. Loss of p53 function occurs in most human tumours by either mutation of TP53 itself or by inactivation of the p53 signal transduction pathway.
2. In many tumours p53 is inactivated by the overexpression of the negative regulators MDM2 and MDM4 or by the loss of activity of the MDM2 inhibitor ARF. The pathway can be reactivated in these tumours by small molecules that inhibit the interaction of MDM2 and/or MDM4 with p53. Such molecules are now in clinical trials.
3. Cell-based screens have been used to find several new non-genotoxic activators of the p53 response, which include inhibitors of protein deacetylating enzymes.
4. Molecules that bind and stabilize mutant p53 — restoring wild-type function — have been discovered by both structure-based design and cell-based screens.
5. Activating a p53-dependent cell cycle arrest in normal cells and tissues can protect them from the toxic effect of anti-mitotic drugs while not reducing their efficacy in killing p53 mutant tumour cells. This drug combination approach represents a new way to exploit the p53 system.
6. The intense study of the p53 pathway is helping to develop new paradigms in drug discovery and development that will have widespread application in other areas of drug discovery.

要点翻译：

1. p53通过响应癌基因激活、DNA损伤及其他应激信号，诱导细胞周期停滞、衰老和凋亡，从而发挥"基因组守护者"的功能。在大多数人类肿瘤中，p53功能会因TP53自身突变或p53信号转导通路失活而丧失。
2. 在许多肿瘤中，p53因负调控因子MDM2和MDM4的过度表达，或MDM2抑制剂ARF的活性缺失而失活。通过小分子化合物抑制MDM2和/或MDM4与p53的相互作用，可重新激活该通路。此类分子目前已进入临床试验阶段。
3. 基于细胞的筛选系统已发现多种新型非基因毒性p53反应激活剂，包括蛋白质去乙酰化酶抑制剂。
4. 通过基于结构的设计和细胞筛选系统，研究人员还发现了能够结合并稳定突变型p53、使其恢复野生型功能的分子。
5. 在正常细胞和组织中激活p53依赖性细胞周期阻滞，可使其免受抗有丝分裂药物的毒性影响，同时不影响这些药物杀伤p53突变肿瘤细胞的疗效。这种药物组合策略为p53系统的应用开辟了新途径。
6. 对p53通路的深入研究正推动药物发现与开发新范式的建立，这些范式将在药物发现的其他领域获得广泛应用。

英文摘要：

Currently, around 11 million people are living with a tumour that contains an inactivating mutation of TP53 (the human gene that encodes p53) and another 11 million have tumours in which the p53 pathway is partially abrogated through the inactivation of other signalling or effector components. The p53 pathway is therefore a prime target for new cancer drug development, and several original approaches to drug discovery that could have wide applications to drug development are being used. In one approach, molecules that activate p53 by blocking protein–protein interactions with MDM2 are in early clinical development. Remarkable progress has also been made in the development of p53-binding molecules that can rescue the function of certain p53 mutants. Finally, cell-based assays are being used to discover compounds that exploit the p53 pathway by either seeking targets and compounds that show synthetic lethality with TP53 mutations or by looking for non-genotoxic activators of the p53 response.

摘要翻译： 

目前，约有1100万人携带有TP53失活突变的肿瘤，另有1100万人的肿瘤因其他信号或效应组分的失活导致p53通路部分失效。因此，p53通路成为新型抗癌药物开发的首要靶点，若干具有广泛药物开发应用前景的原创性药物发现策略正在推进。其中一种策略是通过阻断与MDM2的蛋白-蛋白相互作用来激活p53的分子，已进入早期临床开发阶段。在开发能够恢复某些p53突变体功能的p53结合分子方面也取得了显著进展。最后，基于细胞的检测方法正被用于发现利用p53通路的化合物，具体包括寻找与TP53突变具有合成致死效应的靶点和化合物，或寻找可非基因毒性地激活p53反应的化合物。

原文链接：

Awakening guardian angels: drugging the p53 pathway