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.
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Supported by F. Hoffmann-La Roche Ltd. Support for third-party writing assistance for this paper—by Kia C. E. Walcott, Ph.D., of Health Interactions, Inc.—was provided by F. Hoffmann-La Roche, Ltd.
Conflict of interest
MK has received research support and advisory or consultancy fees from Roche/Genentech and AbbVie. GM has no conflict of interests to disclose. ND has received grants and personal fees from Genentech, Pfizer, AbbVie, Astellas, Bristol Myers Squibb, Agios, Immunogen, Servier, and Daiichi Sankyo; grants from Novimmune; and personal fees from Jazz. CP has no conflict of interests to disclose. AW has received honoraria from and held consulting or advisory roles for Novartis, Astellas, Pfizer, MacroGenics, AbbVie, Genentech, Servier, Celgene, Amgen, AstraZeneca, and Janssen; been part of the speakers bureau for AbbVie, Genentech and Novartis; received research funding from Novartis, Celgene, AbbVie, Servier, AstraZeneca and Amgen; and is a former employee of the Walter and Eliza Hall Institute and receives a part of their royalty stream related to venetoclax. BH is a full-time employee of Roche and owns stock in the company. MO is a full-time employee of Roche and owns stock in the company. JM has received grants and personal fees from Roche, Incyte, Promedior, PharmaEssentia; grants from Kartos, Novartis, Merck, CTI Biopharma, and Janssen; and personal fees from Celgene and AbbVie. MA has received research support from Daiichi Sankyo.
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Konopleva, M., Martinelli, G., Daver, N. et al. MDM2 inhibition: an important step forward in cancer therapy. Leukemia 34, 2858–2874 (2020). https://doi.org/10.1038/s41375-020-0949-z
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