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Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound

Abstract

The tumor suppressor p53 inhibits tumor growth primarily through its ability to induce apoptosis. Mutations in p53 occur in at least 50% of human tumors. We hypothesized that reactivation of mutant p53 in such tumors should trigger massive apoptosis and eliminate the tumor cells. To test this, we screened a library of low-molecular-weight compounds in order to identify compounds that can restore wild-type function to mutant p53. We found one compound capable of inducing apoptosis in human tumor cells through restoration of the transcriptional transactivation function to mutant p53. This molecule, named PRIMA-1, restored sequence-specific DNA binding and the active conformation to mutant p53 proteins in vitro and in living cells. PRIMA-1 rescued both DNA contact and structural p53 mutants. In vivo studies in mice revealed an antitumor effect with no apparent toxicity. This molecule may serve as a lead compound for the development of anticancer drugs targeting mutant p53.

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Figure 1: Identification and properties of PRIMA-1.
Figure 2: PRIMA-1 induces cell death by apoptosis.
Figure 3: Effect of PRIMA-1 on the conformation of mutant p53 proteins.
Figure 4: Effect of PRIMA-1 on the DNA binding of mutant p53 proteins.
Figure 5: Restoration of transcriptional transactivation activity to mutant p53 by PRIMA-1.
Figure 6: Tumor suppression by PRIMA-1.

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Acknowledgements

We thank M. Fritsche for Saos-2-His-273 cells; B. Vogelstein for HCT-116 cells; E. Lukanidin for the p53-pfLUC plasmid; M. Rodensjö for the preparation of histological sections; and the Drug Synthesis & Chemistry Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, NCI, for the library of low-molecular-weight compounds. This study was supported by project grants from the Swedish Cancer Society (Cancerfonden), the Swedish Medical Research Council, the Swedish Royal Academy of Sciences and the European Union 5th Framework Program. V.J.N.B. was supported by a postdoctoral fellowship from the Swedish Cancer Society.

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Correspondence to Klas G. Wiman.

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Bykov, V., Issaeva, N., Shilov, A. et al. Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound. Nat Med 8, 282–288 (2002). https://doi.org/10.1038/nm0302-282

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