Cancer is a leading cause of death worldwide. It initiates when cell cycle regulatory genes lose their function either by environmental and/or by internal factors. Tumor suppressor protein p53, known as “Guardian of genome”, plays a central role in maintaining genomic stability of the cell. Mutation of TP53 is documented in more than 50% of human cancers, usually by overexpression of negative regulator protein MDM2. Hence, reactivation of p53 by blocking the protein-protein interaction between the murine double minute 2 (MDM2) and the tumor suppressor protein p53 has become the most promising therapeutic strategy in oncology. Several classes of small molecules have been identified as potent, selective and efficient p53-MDM2 inhibitors. Herein, we review the druggability of p53-MDM2 inhibitors and their optimization approaches as well as clinical candidates categorized by scaffold type.

癌症是全球主要的死亡原因。当细胞周期调节基因由于环境和/或内部因素而失去功能时，它会启动。肿瘤抑制蛋白p53，被称为“基因组守护者”，在维持细胞基因组稳定性中起着核心作用。超过53％的人类癌症中记录了TP53的突变，通常是由于负调控蛋白MDM2的过表达。因此，通过阻断鼠双分2（MDM2）和抑癌蛋白p53之间的蛋白质相互作用来重新激活p53已成为肿瘤学中最有希望的治疗策略。几类小分子已被鉴定为有效，选择性和有效的p53-MDM2抑制剂。在这里