Abstract Small-molecule modulation of protein-protein interactions (PPIs) is a very promising but also challenging area in drug discovery. The tumor suppressor protein p53 is one of the most frequently altered proteins in human cancers, making it an attractive target in oncology. 14-3-3 proteins have been shown to bind to and positively regulate p53 activity by protecting it from MDM2-dependent degradation or activating its DNA binding affinity. PPIs can be modulated by inhibiting or stabilizing specific interactions by small molecules. Whereas inhibition has been widely explored by the pharmaceutical industry and academia, the opposite strategy of stabilizing PPIs still remains relatively underexploited. This is rather interesting considering the number of natural compounds like rapamycin, forskolin and fusicoccin that exert their activity by stabilizing specific PPIs. In this review, we give an overview of 14-3-3 interactions with p53, explain isoform specific stabilization of the tumor suppressor protein, explore the approach of stabilizing the 14-3-3σ-p53 complex and summarize some promising small molecules inhibiting the p53-MDM2 protein-protein interaction.

中文翻译：

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p53 蛋白-蛋白相互作用的小分子调节

摘要 蛋白质-蛋白质相互作用 (PPI) 的小分子调节是药物发现中一个非常有前途但也具有挑战性的领域。肿瘤抑制蛋白 p53 是人类癌症中最常改变的蛋白质之一，使其成为肿瘤学中一个有吸引力的目标。14-3-3 蛋白已被证明通过保护 p53 免受 MDM2 依赖性降解或激活其 DNA 结合亲和力来结合并积极调节 p53 活性。PPI 可以通过抑制或稳定小分子的特定相互作用来调节。尽管制药业和学术界已经广泛探索了抑制作用，但稳定 PPI 的相反策略仍然相对未充分利用。考虑到雷帕霉素等天然化合物的数量，这相当有趣，forskolin 和 fusicoccin 通过稳定特定的 PPI 发挥其活性。在这篇综述中，我们概述了 14-3-3 与 p53 的相互作用，解释了肿瘤抑制蛋白的同种型特异性稳定性，探索了稳定 14-3-3σ-p53 复合物的方法，并总结了一些有希望的小分子抑制肿瘤抑制蛋白p53-MDM2 蛋白质-蛋白质相互作用。