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Targeting MDM2 for the development of a new cancer therapy: progress and challenges

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Abstract

For much of the past 20 years, MDM2 has been pursued as a cancer therapeutic target. Small molecule inhibitors that block the MDM2-p53 protein-protein interaction (MDM2 inhibitors) have been developed and a number of them have been evaluated in clinical trials for cancer treatment. Notwithstanding various setbacks, several MDM2 inhibitors have now progressed into late-stage clinical development. New strategies have also been developed to enhance the efficacy of MDM2 inhibitors and to mitigate their on-target toxicity. In this review, we summarize the progress and challenges in the development of a MDM2 targeted therapy.

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Authors and Affiliations

  1. Departments of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA

    Angelo Aguilar, Junius E. Thomas & Shaomeng Wang

  2. Departments of Program in Chemical Biology, University of Michigan, Ann Arbor, MI, 48109, USA

    Junius E. Thomas & Shaomeng Wang

  3. Departments of Pharmacology, University of Michigan, Ann Arbor, MI, 48109, USA

    Shaomeng Wang

  4. Departments of Medicinal Chemistry, University of Michigan, Ann Arbor, MI, 48109, USA

    Shaomeng Wang

  5. Departments of Rogel Cancer Center, University of Michigan, Ann Arbor, MI, 48109, USA

    Shaomeng Wang

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  1. Angelo Aguilar
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Correspondence to Shaomeng Wang.

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Conflict of interest

SW and AA are co-inventors of an MDM2 inhibitor APG-115 and MDM2 degraders, which have been licensed by Ascentage Pharma Group for clinical development and they receive royalty from the University of Michigan. SW is a co-founder of Ascentage, owns stock in Ascentage and is a paid consultant of Ascentage. The University of Michigan also has a research contract with Ascentage.

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Aguilar, A., Thomas, J.E. & Wang, S. Targeting MDM2 for the development of a new cancer therapy: progress and challenges. Med Chem Res 32, 1334–1344 (2023). https://doi.org/10.1007/s00044-023-03102-1

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