p53 Laboratory (A-STAR), 8A Biomedical Grove, Immunos, Singapore 138648.
Nat Rev Cancer. 2009 Dec;9(12):862-73. doi: 10.1038/nrc2763.
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.
目前，大约有 1100 万人患有肿瘤，其中包含 TP53（编码 p53 的人类基因）的失活突变，另有 1100 万人的肿瘤中 p53 途径通过其他信号或效应子成分的失活而部分被废除。因此，p53 途径是新癌症药物开发的主要目标，并且正在使用几种可能广泛适用于药物开发的原始药物发现方法。在一种方法中，通过阻断与 MDM2 的蛋白-蛋白相互作用来激活 p53 的分子正在早期临床开发中。在开发能够挽救某些 p53 突变体功能的 p53 结合分子方面也取得了显著进展。最后，正在使用基于细胞的测定法来发现通过与 TP53 突变显示合成致死性或寻找非遗传毒性的 p53 反应激活剂来利用 p53 途径的化合物。
