Department of Chemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada.
Inserm UMR_S 1113, Université de Strasbourg, Molecular Mechanisms of Stress Response and Pathologies, ITI InnoVec, Strasbourg, France.
Chem Soc Rev. 2020 Oct 5;49(19):6995-7014. doi: 10.1039/d0cs00163e.
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.
被称为“基因组的守护者”，p53 是癌症中突变最频繁的蛋白质，几乎所有癌症都表现出 p53 途径的功能障碍。作为一个过表达和肿瘤特异性的靶点，过去二十年中，人们致力于开发旨在恢复突变型 p53 野生型功能的小分子。在这篇综述中，我们收集和传达了小分子药物设计中涉及的化学原理，用于抗癌治疗中的错误折叠蛋白质。虽然这种方法遇到了重大挑战，包括非靶点机制，这些机制会导致 p53 状态无关的细胞毒性，但基因测序能力的重大技术进步和向个性化医疗的转变为 p53 激活化合物带来了重大希望，并可能为癌症治疗领域带来广泛的好处。
