Small-molecule MDM2 inhibitors in clinical trials for cancer therapy

• Published in: European journal of medicinal chemistry 2022-06, Vol.236, p.114334-114334, Article 114334
• Main Authors: Wang, Shuai, Chen, Fen-Er
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemistry; Cancer therapy; Clinical trials; Humans; MDM2 inhibitors; MDM2-p53 protein-protein interaction; Neoplasms - drug therapy; Protein Binding; Proto-Oncogene Proteins c-mdm2 - metabolism; Tumor Suppressor Protein p53 - metabolism
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2022.114334

Disruption of the MDM2-p53 protein-protein interaction by small-molecule inhibitors has been highly pursued by many academic laboratories and pharmaceutical companies as a promising strategy for cancer therapy. To date, based on the explanation of the cocrystal structure of MDM2 with p53, many highly potent and selective small-molecule MDM2 inhibitors have been successfully discovered and nine of them are currently under different clinical trials for cancer therapy. Herein, we will review the function of MDM2 and provide a comprehensive and updated overview of small-molecule MDM2 inhibitors in different clinical phases for cancer therapy, especially focusing on the identification and optimization, and preclinical/clinical studies of these clinical-stage MDM2 inhibitors. Challenges regarding acquired resistance and potential toxicity of MDM2 inhibitors to normal tissues and outlook are also briefly discussed, which will further guide the design of new small-molecule MDM2 inhibitors. [Display omitted] •Nine small-molecule MDM2 inhibitors in clinical phases for cancer therapy are summarized.•Identification and optimization of MDM2 inhibitors and preclinical/clinical studies are highlighted.•Challenges and outlook are briefly discussed to guide future design of small-molecule MDM2 inhibitors.