Since the discovery of the first MDM2 inhibitors, we have gained deeper insights into the cellular roles of MDM2 and p53. In this review, we focus on MDM2 inhibitors that bind to the p53-binding domain of MDM2 and aim to disrupt the binding of MDM2 to p53. We describe the basic mechanism of action of these MDM2 inhibitors, such as nutlin-3a, summarise the determinants of sensitivity to MDM2 inhibition from p53-dependent and p53-independent points of view and discuss the problems with innate and acquired resistance to MDM2 inhibition. Despite progress in MDM2 inhibitor design and ongoing clinical trials, their broad use in cancer treatment is not fulfilling expectations in heterogenous human cancers. We assess the MDM2 inhibitor types in clinical trials and provide an overview of possible sources of resistance to MDM2 inhibition, underlining the need for patient stratification based on these aspects to gain better clinical responses, including the use of combination therapies for personalised medicine.

• Keywords
• Combination therapy, MDM2, MDM2 inhibitor, Nutlin-3a, Personalised medicine, Resistance, p53,
• MeSH
• Drug Resistance, Bacterial drug effects   physiology   MeSH
• Molecular Targeted Therapy methods   MeSH
• Clinical Trials as Topic MeSH
• Humans MeSH
• Tumor Suppressor Protein p53 antagonists & inhibitors   genetics   metabolism   MeSH
• Neoplasms drug therapy   MeSH
• Antineoplastic Agents pharmacology   MeSH
• Proto-Oncogene Proteins c-mdm2 antagonists & inhibitors   genetics   metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• MDM2 protein, human MeSH Browser
• Tumor Suppressor Protein p53 MeSH
• Antineoplastic Agents MeSH
• Proto-Oncogene Proteins c-mdm2 MeSH
• TP53 protein, human MeSH Browser