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Small-Molecule Inhibitors of Protein-Protein Interactions pp 151–172Cite as

Small-Molecule Inhibitors of the p53-MDM2 Interaction

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Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 348))

Abstract

The p53 tumor suppressor is controlled by MDM2, which binds p53 and negatively regulates its transcriptional activity and stability. Many tumors overproduce MDM2 to impair p53 function. Therefore, restoration of p53 activity by inhibiting the p53–MDM2 binding represents an attractive novel approach to cancer therapy. Recently developed potent and selective small-molecule antagonists of the p53–MDM2 interaction have been used to demonstrate the proof-of-concept for this approach. These compounds interact specifically with the p53-binding pocket of MDM2 and release p53 from negative control. Treatment of cancer cells expressing wild-type p53 stabilize p53 and activate the p53 pathway, leading to cell cycle arrest and apoptosis. In mice-bearing established human tumor xenografts, MDM2 antagonists caused tumor inhibition and regression at nontoxic concentrations, suggesting that they may have a therapeutic utility in the treatment of cancer. An increasing number of MDM2 antagonists are being generated and some of them have entered clinical trials. Here, we review this class of emerging drugs with an emphasis on small molecules that inhibit the p53–MDM2 interaction.

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  1. Roche Research Center, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ, 07110, USA

    Binh T. Vu & Lyubomir Vassilev

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  1. Binh T. Vu
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  1. Roche Research Center, Dept. Discovery Oncology, Hoffmann-La Roche Inc., Kingsland Street 340, Nutley, 07110-1199, New Jersey, USA

    Lyubomir Vassilev

  2. Roche Research Center, Dept. of Discovery Oncology, Hoffmann-La Roche Inc., Kingsland Street 340, Nutley, 07110, New Jersey, USA

    David Fry

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Vu, B.T., Vassilev, L. (2010). Small-Molecule Inhibitors of the p53-MDM2 Interaction. In: Vassilev, L., Fry, D. (eds) Small-Molecule Inhibitors of Protein-Protein Interactions. Current Topics in Microbiology and Immunology, vol 348. Springer, Berlin, Heidelberg. https://doi.org/10.1007/82_2010_110

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