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Review
. 2004 Oct 18;91(8):1415-9.
doi: 10.1038/sj.bjc.6602164.

Targeting the p53-MDM2 interaction to treat cancer

C Klein  1 , L T Vassilev
Affiliations
Review

Targeting the p53-MDM2 interaction to treat cancer

C Klein et al. Br J Cancer. .

Abstract

The tumour suppressor p53 is a transcription factor with powerful antitumour activity that is controlled by its negative regulator MDM2 (mouse double minute 2, also termed HDM2 in humans) through a feedback mechanism. MDM2, which is overproduced in many tumours, binds p53 and inhibits its function by modulating its transcriptional activity and stability. Activation of p53 in tumour cells by inhibiting its physical interaction with MDM2 has been in the focus of cancer drug discovery. However, development of nonpeptidic MDM2 antagonists turned out to be challenging. Recently, the first potent and selective small-molecule antagonists of MDM2, the Nutlins, have been identified. Studies with Nutlins provided in vitro and in vivo proof-of-principle for targeting p53-MDM2 interaction for cancer therapy.

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Figures

Figure 1
Figure 1
Small-molecule inhibitors of p53–MDM2 binding. (A) Chalcone, (B) boronic–chalcone, (C) Chlorofusin, and (D) Nutlin-2.
Figure 2
Figure 2
Nutlins bind MDM2 at the p53-binding pocket. Surface representation of MDM2–Nutlin-2 interaction. The p53 binding area within 6 Å distance from Nutlin-2 is depicted in yellow and Nutlin-2 in green. Nutlin-2 is rotated out of the p53-binding pocket in the lower panel. Coordinates are derived from the crystal structure of MDM2–Nutlin-2 complex (Vassilev et al, 2004).
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