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Therapeutics

Unleashing p53

Nature Reviews Cancer volume 4, page 94 (2004)Cite this article

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Protein–protein interactions have traditionally been viewed as highly challenging targets for small-molecule drug discovery, owing to issues such as the lack of well-defined binding pockets at the interface. However, the crystal structure of MDM2 bound to a peptide from the transactivation domain of p53 revealed that MDM2 possesses a relatively deep pocket that is filled by a helical region of the p53 peptide, raising the hope of identifying small molecules capable of binding in the pocket instead of p53. Vassilev and colleagues therefore screened a diverse library of compounds for their ability to inhibit the binding of MDM2 to p53 using surface plasmon resonance,which is well-suited to analysing protein–protein interactions, and discovered a series of cis-imidazoline analogues that displace p53 from its complex with MDM2 with IC50s in the nanomolar range. A crystal structure of one of the compounds in complex with MDM2 confirmed that it bound in the p53-binding site.

Testing the imidazoline analogues in a range of cancer-cell-based assays provided strong evidence that they activated the p53 pathway, leading to cell-cycle arrest and apoptosis. Encouraged by this, the authors assessed whether one of the analogues could suppress the growth of established tumour xenografts in mice. Oral administration of the compound, which was well-tolerated, resulted in 90% inhibition of tumour growth relative to vehicle controls, compared with 81% inhibition using intravenous administration of the maximal tolerated dose of the traditional cytotoxic drug doxorubicin.

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References

ORIGINAL RESEARCH PAPER

  1. Vassilev, L. T. et al. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 2 Jan 2004 (doi: 10.1126/science.1092472)

FURTHER READING

  1. Chène, P. Inhibiting the p53-MDM2 interaction: an important target for cancer therapy. Nature Rev. Cancer 3, 102–109 (2003)

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Authors
  1. Peter Kirkpatrick
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Kirkpatrick, P. Unleashing p53. Nat Rev Cancer 4, 94 (2004). https://doi.org/10.1038/nrc1293

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  • DOI: https://doi.org/10.1038/nrc1293

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