Abstract：
Proteolysis-targeting chimeras (PROTACs) are molecules that selectively degrade a protein of interest (POI). The incorporation of ligands that recruit mouse double minute 2 (MDM2) into PROTACs, forming the so-called MDM2-based PROTACs, has shown promise in cancer treatment due to its dual mechanism of action: a PROTAC that recruits MDM2 prevents its binding to p53, resulting not only in the degradation of POI but also in the increase of intracellular levels of the p53 suppressor, with the activation of a whole set of biological processes, such as cell cycle arrest or apoptosis. In addition, these PROTACs, in certain cases, allow for the degradation of the target, with nanomolar potency, in a rapid and sustained manner over time, with less susceptibility to the development of resistance and tolerance, without causing changes in protein expression, and with selectivity to the target, including the respective isoforms or mutations, and to the cell type, overcoming some limitations associated with the use of inhibitors for the same therapeutic target. Therefore, the aim of this review is to analyze and discuss the characteristics of MDM2-based PROTACs developed for the degradation of oncogenic proteins and to understand what potential they have as future anticancer drugs.
摘要：
蛋白水解靶向嵌合体(PROTAC)是选择性降解感兴趣的蛋白质(POI)的分子。将招募小鼠双分钟2（MDM2）的配体掺入到PROTACs中，形成所谓的基于MDM2的协议，由于其双重作用机制，已在癌症治疗中显示出希望：招募MDM2的PROTAC阻止其与p53的结合，不仅导致POI的降解，而且导致p53抑制剂的细胞内水平增加，随着一整套生物过程的激活，如细胞周期停滞或凋亡。此外,这些PROTACs,在某些情况下,允许目标的退化，具有纳摩尔效力，随着时间的推移，以快速和持续的方式，对抗性和耐受性发展的敏感性较低，而不会引起蛋白质表达的变化，并且对目标有选择性，包括各自的同工型或突变，和细胞类型，克服了与针对相同治疗靶标使用抑制剂相关的一些限制。因此,这篇综述的目的是分析和讨论为降解致癌蛋白而开发的基于MDM2的PROTACs的特征，并了解它们作为未来抗癌药物的潜力。
