amg-232 and Neoplasms

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.

Topics: Antineoplastic Agents; Humans; Neoplasms; Protein Binding; Proto-Oncogene Proteins c-mdm2; Tumor Suppressor Protein p53

In tumor cells, p53 is always inactivated due to the mutation or deletion of TP53 gene or inhibited by the overexpressed MDM2. Small-molecule induced restoring of p53 function by blocking MDM2-p53 protein-protein interactions has been highly pursued as an attractive therapeutic strategy for cancer therapy. To date, a large number of small-molecule inhibitors have been identified based on the compact and well-defined MDM2-p53 interactions, of which SAR405838, MK-8242, DS-3032b, NVP-CGM097, RG7112, HDM201, RG7388, ALRN-6924 and AMG 232 are undergoing clinical assessment at different phases for cancer therapy. This review is focused on the discovery and development of piperidinone-based MDM2-p53 inhibitors for cancer therapy, including the identification of hit compounds, hit-to-lead optimizations, binding models of ligands in the active site of MDM2, metabolic studies, and preclinical data of advanced piperidinone-based MDM2-p53 inhibitors. Additionally, acquired resistance of MDM2 inhibitors and potential toxicity toward normal tissues are briefly discussed.

Topics: Dose-Response Relationship, Drug; Humans; Ligands; Molecular Structure; Neoplasms; Piperidones; Protein Binding; Proto-Oncogene Proteins c-mdm2; Structure-Activity Relationship; Tumor Suppressor Protein p53