文章：

靶向突变p53的有效癌症治疗

Targeting mutant p53 for efficient cancer therapy

原文发布日期：2017-12-15

DOI: 10.1038/nrc.2017.109

类型: Review Article

开放获取: 否

要点：

1. The TP53 tumour suppressor gene is mutated in close to half of all human tumours
2. Most TP53 mutations are missense mutations leading to single amino acid substitutions in the p53 protein
3. Small molecules that reactivate missense-mutant p53 and induce tumour cell death have been identified by various approaches
4. Two mutant-p53-reactivating compounds are being tested in clinical trials
5. Reactivation of nonsense-mutant TP53 by induction of translational readthrough has been demonstrated with aminoglycoside antibiotics
6. Novel anticancer drugs that reactivate mutant p53 should have wide clinical applicability

要点翻译：

1. TP53肿瘤抑制基因在近半数人类肿瘤中发生突变
2. 大多数TP53突变为错义突变，导致p53蛋白中的单个氨基酸替换
3. 通过多种方法已发现能重新激活错义突变p53并诱导肿瘤细胞死亡的小分子
4. 两种突变p53再激活化合物正在临床试验中进行测试
5. 氨基糖苷类抗生素已证实可通过诱导翻译通读来恢复无义突变TP53的功能
6. 重新激活突变p53的新型抗癌药物应具有广泛的临床适用性

英文摘要：

The tumour suppressor gene TP53 is the most frequently mutated gene in cancer. Wild-type p53 can suppress tumour development by multiple pathways. However, mutation of TP53 and the resultant inactivation of p53 allow evasion of tumour cell death and rapid tumour progression. The high frequency of TP53 mutation in tumours has prompted efforts to restore normal function of mutant p53 and thereby trigger tumour cell death and tumour elimination. Small molecules that can reactivate missense-mutant p53 protein have been identified by different strategies, and two compounds are being tested in clinical trials. Novel approaches for targeting TP53 nonsense mutations are also underway. This Review discusses recent progress in pharmacological reactivation of mutant p53 and highlights problems and promises with these strategies.

摘要翻译： 

抑癌基因TP53是癌症中最常发生突变的基因。野生型p53可通过多条通路抑制肿瘤发展；然而，TP53突变导致p53失活，使肿瘤细胞得以逃避死亡并加速进展。由于TP53突变在肿瘤中频率极高，研究者致力于恢复突变p53的正常功能，从而诱导肿瘤细胞死亡并清除肿瘤。通过不同策略，已发现能够重新激活错义突变p53蛋白的小分子化合物，其中两种正在临床试验中接受评估；针对TP53无义突变的新方法也在推进之中。本综述讨论了在药理学上重新激活突变p53的最新进展，并指出了这些策略所面临的问题与前景。

原文链接：

Targeting mutant p53 for efficient cancer therapy