主要肿瘤抑制蛋白 p53 的活性在几乎所有人类癌症类型中都受到破坏，原因可能是 TP53 基因突变或其负调节因子小鼠双分钟 2 (MDM2) 的过度表达。 MDM2 及其同源物 MDM4 与基于不同化学物质的抑制剂一起释放 p53，为广泛的非基因毒性抗癌疗法开辟了前景。本文回顾了 2019 年至 2023 年 MDM2-p53 领域的专利和专利申请相互作用抑制剂。在 Espacenet、Google Patents 和 Pubmed 中搜索到的新报道的分子分为五类：具有单环、多环或螺吲哚支架的化合物、肽衍生物和蛋白水解靶向嵌合体 (PROTAC)。文章还介绍了各种结构的MDM2拮抗剂在招募或已完成的癌症临床试验中的进展。尽管自首创小分子抑制剂Nutlin-3发现后经过二十年的深入研究，但尚未有针对MDM2的药物- p53互动已上市。尽管如此，仍有十多种化合物在临床中进行评估，无论是作为独立药物还是与其他靶向疗法或标准化疗药物联合使用，其中包括两种处于 3 期研究中的抑制剂和两种被 FDA 授予孤儿药/快速通道资格的化合物。

The activity of the major tumor suppressor protein p53 is disrupted in nearly all human cancer types, either by mutations in TP53 gene or by overexpression of its negative regulator, Mouse Double Minute 2 (MDM2). The release of p53 from MDM2 and its homolog MDM4 with inhibitors based on different chemistries opened up a prospect for a broad, non-genotoxic anticancer therapy.This article reviews the patents and patent applications between years 2019 and 2023 in the field of MDM2-p53 interaction inhibitors. The newly reported molecules searched in Espacenet, Google Patents and Pubmed were grouped into five general categories: compounds having single-ring, multi-ring or spiro-oxindole scaffolds, peptide derivatives and proteolysis-targeting chimeras (PROTACs). The article also presents the progress of MDM2 antagonists of various structures in recruiting or completed cancer clinical trials.Despite twenty years of intensive studies after the discovery of the first-in-class small-molecule inhibitor, Nutlin-3, no drugs targeting MDM2-p53 interaction have reached the market. Nevertheless, more than ten compounds are still evaluated in clinics, both as standalone drugs and in combinations with other targeted therapies or standard chemotherapy agents, including two inhibitors in phase 3 studies and two compounds granted orphan-drug/fast-track designation by the FDA.