Small-molecule MDM2 inhibitors in clinical trials for cancer therapy.

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.