Department of Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, PSC304A, Los Angeles, California 90089, USA.
Expert Opin Ther Pat. 2006 Feb;16(2):165-88. doi: 10.1517/13543776.16.2.165.
The interaction between p53 and murine double minute 2 (MDM2) provides an attractive drug target in oncology. Small molecule inhibitors of this interaction have not only provided strong evidence for blocking the protein-protein interaction, but are also extremely useful as biological probes and ultimately as novel therapeutics. Here, a comprehensive review of the patented small molecule inhibitors of the p53-MDM2 interaction are provided. These inhibitors are divided into eight classes of compounds that include cis-imidazolines, benzodiazepines, fused indoles, substituted piperazines, substituted piperidines, aryl boronic acids, spiro-indoles, and alpha-helix mimetic compounds. The best documented class of compounds, cis-imidazolines (e.g., Nutlins) are selective and potent inhibitors of the p53-MDM2 interaction, and selected examples exhibit potency in the nanomolar range. Nutlins induce apoptosis in p53 wild-type cells and show in vivo efficacy in mice xenograft models. Additional strategies briefly discussed in this review, and which are under current exploration in targeting the p53 pathway, include the inhibition of MDM2-mediated p53 ubiquitylation and restoration of DNA-binding activity of mutant p53 protein using small molecules.
p53 和鼠双微体 2（MDM2）之间的相互作用为肿瘤学提供了一个有吸引力的药物靶点。这种相互作用的小分子抑制剂不仅为阻断蛋白-蛋白相互作用提供了有力证据，而且作为生物探针也非常有用，并最终成为新的治疗方法。在这里，提供了对 p53-MDM2 相互作用的已授权小分子抑制剂的全面综述。这些抑制剂分为八类化合物，包括顺式咪唑啉类、苯并二氮杂䓬类、稠合吲哚类、取代哌嗪类、取代哌啶类、芳基硼酸类、螺吲哚类和α-螺旋模拟化合物。顺式咪唑啉类（例如，Nutlins）是 p53-MDM2 相互作用的选择性和有效抑制剂，有选择的例子在纳摩尔范围内表现出效力。Nutlins 诱导 p53 野生型细胞凋亡，并在小鼠异种移植模型中显示出体内疗效。在本综述中简要讨论的其他策略，以及目前正在探索靶向 p53 途径的策略，包括抑制 MDM2 介导的 p53 泛素化和使用小分子恢复突变型 p53 蛋白的 DNA 结合活性。
