Referred to as the “guardian of the genome”, p53 is the most frequently mutated protein in cancer and almost all cancers exhibit malfunction along the p53 pathway. As an overexpressed and tumour-specific target, the past two decades have seen considerable dedication to the development of small molecules that aim to restore wild-type function in mutant p53. In this review we collect and communicate the chemical principles involved in small molecule drug design for misfolded proteins in anticancer therapy. While this approach has met with significant challenges including off-target mechanisms that induce cytotoxicity independent of p53 status, major technological advancements in gene sequencing capability and a shift towards personalized medicine holds significant promise for p53 reactivating compounds and could have widespread benefits for the field of cancer therapy.

中文翻译：

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一种平衡的行为：使用小分子对癌症中的p53途径进行治疗性干预。

p53被称为“基因组的守护者”，是癌症中最常见的突变蛋白，几乎所有癌症都沿p53途径表现出功能异常。作为过表达且特定于肿瘤的靶标，在过去的二十年中，人们致力于开发旨在恢复突变型p53中野生型功能的小分子。在这篇综述中，我们收集并交流了抗癌治疗中错误折叠的蛋白质的小分子药物设计所涉及的化学原理。尽管此方法遇到了重大挑战，包括脱靶机制（其诱导了独立于p53状态的细胞毒性），