Blocking the MDM2/X–P53 protein–protein interaction has been widely recognized as an attractive therapeutic strategy for the treatment of cancers. Numerous small-molecule MDM2 inhibitors have been reported since the release of the structure of the MDM2–P53 interaction in 1996, SAR405838, NVP-CGM097, MK-8242, RG7112, RG7388, DS-3032b, and AMG232 currently undergo clinical evaluation for cancer therapy. This review is intended to provide a comprehensive and updated overview of MDM2 inhibitors and proteolysis targeting chimera (PROTAC) degraders with a particular focus on how these inhibitors or degraders are identified from starting points, strategies employed, structure–activity relationship (SAR) studies, binding modes or co-crystal structures, biochemical data, mechanistic studies, and preclinical/clinical studies. Moreover, we briefly discuss the challenges of designing MDM2/X inhibitors for cancer therapy such as dual MDM2/X inhibition, acquired resistance and toxicity of P53 activation as well as future directions.

阻断MDM2 / X-P53蛋白之间的相互作用已被广泛认为是治疗癌症的一种有吸引力的治疗策略。自从1996年MDM2-P53相互作用的结构释放以来，已经报道了许多小分子MDM2抑制剂，SAR405838，NVP-CGM097，MK-8242，RG7112，RG7388，DS-3032b和AMG232目前正在接受癌症的临床评估治疗。这篇评论旨在提供针对MDM2抑制剂和针对嵌合体（PROTAC）降解蛋白的蛋白酶的全面，更新的概述，特别着重于如何从起点，采用的策略，结构-活性关系（SAR）研究中鉴定出这些抑制剂或降解剂，结合模式或共晶体结构，生化数据，机理研究以及临床前/临床研究。此外，