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.

抑癌基因TP53是癌症中最常见的突变基因。野生型p53可以通过多种途径抑制肿瘤的发展。然而，TP53的突变和p53的失活可以逃避肿瘤细胞的死亡和肿瘤的快速发展。肿瘤中TP53突变的高频率促使人们努力恢复突变体p53的正常功能，从而触发肿瘤细胞死亡和肿瘤消除。已经通过不同的策略鉴定了可以重新激活错义突变p53蛋白的小分子，并且两种化合物正在临床试验中进行测试。靶向TP53的新方法无意义的突变也在进行中。这篇综述讨论了突变体p53药理学活化的最新进展，并着重指出了这些策略存在的问题和希望。