Targeting Mutant p53 for Improved Cancer Therapy
Pharmacological restoration of wild-type activity to mutant p53 has emerged as a promising strategy for improved cancer therapy. This should restore p53-dependent apoptosis in response to oncogenic stress and thus eliminate the tumor. Mutant p53 reactivation may also lead to inhibition of mutant p53 gain-of-function activities that promote tumor growth, and act synergistically with conventional chemotherapeutic agents and radiotherapy. Several small molecules that target mutant p53 and restore wild-type conformation, and/or preferentially target mutant p53-expressing tumor cells, have been identified. Strategies for identification of such compounds include both rational design, based on detailed structural studies of mutant p53, and random screening of chemical libraries using protein or cellular assays. The mutant p53-reactivating compounds PRIMA-1 and APR-246 (PRIMA-1MET) modify cysteines in the p53 core domain by Michael addition. Mutant versions of p53 family members p63 and p73 can be targeted as well. The safety of APR-246 has been tested in a phase I clinical trial. Further studies should address the molecular mechanism of mutant p53 reactivation in more detail and assess clinical antitumor efficacy.
KeywordsCysteine Prostaglandin Integrin Imatinib Gefitinib
We thank the Swedish Cancer Society (Cancerfonden), the Swedish Medical Research Council (VR), the Cancer Society of Stockholm, the Stockholm County Council (ALF), the EU FP6 framework program, and Karolinska Institutet for generous support. V.J.N.B. and K.G.W. are cofounders and shareholders of the company Aprea AB that develops p53-based cancer therapy including APR-246. K.G.W. is a member of its board.
- Comperat E, Camparo P, Haus R, Chartier-Kastler E, Bart S, Delcourt A, Houlgatte A, Francois R, Capron F, Vieillefond A (2006) Immunohistochemical expression of p63, p53 and MIB-1 in urinary bladder carcinoma. A tissue microarray study of 158 cases. Virchows Arch 448:319–324PubMedCrossRefGoogle Scholar
- Demma M, Maxwell E, Ramos R, Liang L, Li C, Hesk D, Rossman R, Mallams A, Doll R, Liu M et al (2010) SCH529074, a small molecule activator of mutant p53, which binds p53 DNA binding domain (DBD), restores growth-suppressive function to mutant p53 and interrupts HDM2-mediated ubiquitination of wild type p53. J Biol Chem 285:10198–10212PubMedCrossRefGoogle Scholar
- Fry DW, Bridges AJ, Denny WA, Doherty A, Greis KD, Hicks JL, Hook KE, Keller PR, Leopold WR, Loo JA et al (1998) Specific, irreversible inactivation of the epidermal growth factor receptor and erbB2, by a new class of tyrosine kinase inhibitor. Proc Natl Acad Sci USA 95:12022–12027PubMedCrossRefGoogle Scholar
- Kravchenko JE, Ilyinskaya GV, Komarov PG, Agapova LS, Kochetkov DV, Strom E, Frolova EI, Kovriga I, Gudkov AV, Feinstein E, Chumakov PM (2008) Small-molecule RETRA suppresses mutant p53-bearing cancer cells through a p73-dependent salvage pathway. Proc Natl Acad Sci USA 105:6302–6307PubMedCrossRefGoogle Scholar
- North S, Pluquet O, Maurici D, El-Ghissassi F, Hainaut P (2002) Restoration of wild-type conformation and activity of a temperature-sensitive mutant of p53 (p53(V272M)) by the cytoprotective aminothiol WR1065 in the esophageal cancer cell line TE-1. Mol Carcinog 33:181–188PubMedCrossRefGoogle Scholar
- Wu CH, Coumar MS, Chu CY, Lin WH, Chen YR, Chen CT, Shiao HY, Rafi S, Wang SY, Hsu H et al (2010) Design and synthesis of tetrahydropyridothieno[2,3-d]pyrimidine scaffold based epidermal growth factor receptor (EGFR) kinase inhibitors: the role of side chain chirality and Michael acceptor group for maximal potency. J Med Chem 53:7316–7326PubMedCrossRefGoogle Scholar