MDM2 inhibition: an important step forward in cancer therapy

• Published in: Leukemia Vol. 34; no. 11; pp. 2858 - 2874
• Main Authors: Konopleva, Marina, Martinelli, Giovanni, Daver, Naval, Papayannidis, Cristina, Wei, Andrew, Higgins, Brian, Ott, Marion, Mascarenhas, John, Andreeff, Michael
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.11.2020; Nature Publishing Group
• Subjects: 631/67/1059; 692/699/67/1990; Cancer; Cancer Research; Cancer therapies; Care and treatment; Clinical trials; Critical Care Medicine; Health aspects; Hematology; Inhibitors; Intensive; Internal Medicine; Ligases; MDM2 protein; Medicine; Medicine & Public Health; Methods; Molecular targeted therapy; Oncology; Oncology, Experimental; p53 Protein; Review Article; Tumor suppressor genes; Ubiquitin-protein ligase; United States
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/s41375-020-0949-z

Targeting the interaction between tumor suppressor p53 and the E3 ligase MDM2 represents an attractive treatment approach for cancers with wild-type or functional TP53 . Indeed, several small molecules have been developed and evaluated in various malignancies. We provide an overview of MDM2 inhibitors under preclinical and clinical investigation, with a focus on molecules with ongoing clinical trials, as indicated by ClinicalTrials.gov . Because preclinical and clinical exploration of combination strategies is underway, data supporting these combinations are also described. We identified the following molecules for inclusion in this review: RG7112 (RO5045337), idasanutlin (RG7388), AMG-232 (KRT-232), APG-115, BI-907828, CGM097, siremadlin (HDM201), and milademetan (DS-3032b). Information about each MDM2 inhibitor was collected from major congress records and PubMed using the following search terms: each molecule name, “MDM2”and “HDM2.” Only congress records were limited by date (January 1, 2012–March 6, 2020). Special attention was given to available data in hematologic malignancies; however, available safety data in any indication are reported. Overall, targeting MDM2 is a promising treatment strategy, as evidenced by the increasing number of MDM2 inhibitors entering the clinic. Additional clinical investigation is needed to further elucidate the role of MDM2 inhibitors in the treatment of human cancers.