Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Characterization of the p53-rescue drug CP-31398 in vitro and in living cells

Oncogene volume 21, pages 2119–2129 (2002)Cite this article

Abstract

The Pfizer compound CP-31398 has been reported to stabilize the core domain of the tumour suppressor p53 in vitro and be an effective anti-cancer drug by virtue of rescuing destabilized mutants of p53. We did not detect any interaction between the p53 core domain and CP-31398 in vitro by a wide range of quantitative biophysical techniques over a wide range of conditions. CP-31398 did not stabilize p53 in our experiments. However, we found that CP-31398 intercalated with DNA and also altered and destabilized the DNA-p53 core domain complex. We analysed by NMR TROSY the interaction of the domain with a DNA oligomer and identified the changes in the complex on the binding of CP-31398. CP-31398 also decreased sequence-specific DNA binding of wild-type p53 and His-273 mutant p53. CP-31398 had a non-specific toxic effect independent of mutant p53 expression in several cell lines carrying Tet-regulated mutant p53. CP-31398 caused a small increase in MDM-2 expression and a more pronounced p53-independent increase in Bax expression. CP-31398 did, however, induce the PAb1620 epitope (characteristic of native p53) in cells expressing His-175 mutant p53. This was prevented by cycloheximide, suggesting that any stabilizing action of CP-31398 would have to be on newly synthesized p53. One of the unstable mutants that was reported to have been rescued by CP-31398, R249S, does not bind DNA when folded at lower temperatures.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9
Figure 10

Similar content being viewed by others

References

  • Asker C, Wiman KG, Selivanova G . 1999 Biochem. Biophys. Res. Commun. 265: 1–6

  • Bullock AN, Fersht AR . 2001 Nature Rev. Cancer 1: 68–76

  • Bullock AN, Henckel J, DeDecker BS, Johnson CM, Nikolova PV, Proctor MR, Lane DP, Fersht AR . 1997 Proc. Natl. Acad. Sci. USA 94: 14338–14342

  • Bullock AN, Henckel J, Fersht AR . 2000 Oncogene 19: 1245–1256

  • Cho Y, Gorina S, Jeffrey PD, Pavletich NP . 1994 Science 265: 346–355

  • Foster BA, Coffey HA, Morin MJ, Rastinejad F . 1999 Science 286: 2507–2510

  • Hollstein MC, Sidransky D, Vogelstein B, Harris CC . 1991 Science 253: 49–53

  • Jayaraman L, Freulich E, Prives C . 1997 Methods Enzymol. 283: 245–256

  • Ko LJ, Prives C . 1996 Genes Dev. 10: 1054–1072

  • Lee W, Harvey TS, Yin Y, Yau P, Litchfield D, Arrowsmith CH . 1994 Structural Biol. 1: 877–890

  • Nikolova PV, Henckel J, Lane DP, Fersht AR . 1998 Proc. Natl. Acad. Sci. USA 95: 14675–14680

  • Nikolova PV, Wong K-B, DeDecker B, Henckel J, Fersht AR . 2000 EMBO J. 19: 370–378

  • Prives C, Hall PA . 1999 J. Pathol. 187: 112–126

  • Selivanova G, Iotsova V, Kiseleva E, Strom M, Bakalkin G, Grafstrom RC, Wiman KG . 1996 Nucleic Acids Res. 24: 3560–3567

  • Wong KB, DeDecker BS, Freund SM, Proctor MR, Bycroft M, Fersht AR . 1999 Proc. Natl. Acad. Sci. USA 96: 8438–8442

Download references

Acknowledgements

This work was supported by the MRC of the UK, and the Swedish Cancer Society (Cancerfonden). TM Rippin receives a Herchel Smith Student of Organic Chemistry and an MRC scholarship, VJN Bykov is supported by a postdoctoral fellowship from the Swedish Cancer Society. We would like to thank SF Poget, A Ashtekar and K Goode for their expertise and assistance in mass spectrometry and Farzan Rastinejad, Pfizer Central Research, for the gift of CP-31398 and comments on the manuscript.

Author information

Authors and Affiliations

  1. Cambridge University Chemical Laboratory and Cambridge Center for Protein Engineering, MRC Centre, Hills Road, Cambridge, CB2 2QH, UK

    Thomas M Rippin, Stefan M V Freund & Alan R Fersht

  2. Department of Oncology-Pathology, Karolinska Institutet, Cancer Center Karolinska (CCK), R8:04 Karolinska Hospital, SE-171 76, Stockholm, Sweden

    Vladimir J N Bykov, Galina Selivanova & Klas G Wiman

Authors
  1. Thomas M Rippin
    View author publications

    Search author on:PubMed Google Scholar

  2. Vladimir J N Bykov
    View author publications

    Search author on:PubMed Google Scholar

  3. Stefan M V Freund
    View author publications

    Search author on:PubMed Google Scholar

  4. Galina Selivanova
    View author publications

    Search author on:PubMed Google Scholar

  5. Klas G Wiman
    View author publications

    Search author on:PubMed Google Scholar

  6. Alan R Fersht
    View author publications

    Search author on:PubMed Google Scholar

Corresponding author

Correspondence to Alan R Fersht.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rippin, T., Bykov, V., Freund, S. et al. Characterization of the p53-rescue drug CP-31398 in vitro and in living cells. Oncogene 21, 2119–2129 (2002). https://doi.org/10.1038/sj.onc.1205362

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/sj.onc.1205362

Keywords

This article is cited by

Search

Advanced search

Quick links