Abstract
The p53 tumor suppressor pathway blocks tumor development by triggering apoptosis or cellular senescence in response to oncogenic stress. A large fraction of human tumors carry p53 mutations that disrupt DNA binding of p53 and transcriptional regulation of target genes. Reconstitution of wild-type p53 in vivo triggers rapid elimination of tumors. Therefore, pharmacological reactivation of mutant p53 is a promising strategy for novel cancer therapy. Several approaches for identification of small molecules that target mutant p53 have been applied, including rational design and screening of chemical libraries. The compound PhiKan083 binds with high affinity to a crevice created by the Y220C mutation in p53 and stabilizes the mutant protein. The compound PRIMA-1 (p53 reactivation and induction of massive apoptosis) restores wild-type conformation to mutant p53 by binding to the core and induces apoptosis in human tumor cells. The PRIMA-1 analog APR-246 is currently tested in a clinical trial. Successful development of mutant p53-reactivating anticancer drugs should have a major impact on the treatment of cancer.
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Acknowledgements
I thank the Swedish Cancer Society (Cancerfonden), the Swedish Medical Research Council (VR), the Cancer Society of Stockholm (Cancerföreningen) and the EU 6th Framework Program for generous support. I am cofounder and shareholder of Aprea AB, a company that develops p53-based cancer therapy, and member of its board.
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Professor Wiman is cofounder and shareholder of Aprea AB, a start-up company that develops p53-based cancer therapy. He is also a member of its board.
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Wiman, K. Pharmacological reactivation of mutant p53: from protein structure to the cancer patient. Oncogene 29, 4245–4252 (2010). https://doi.org/10.1038/onc.2010.188
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DOI: https://doi.org/10.1038/onc.2010.188
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