title: Pharmacological reactivation of p53 as a strategy to treat cancer.
abstract: It has been confirmed through studies using the technique of unbiased sequencing that the TP53 tumour suppressor is the most frequently inactivated gene in cancer. This finding, together with results from earlier studies, provides compelling evidence for the idea that p53 ablation is required for the development and maintenance of tumours. Genetic reconstitution of the function of p53 leads to the suppression of established tumours as shown in mouse models. This strongly supports the notion that p53 reactivation by small molecules could provide an efficient strategy to treat cancer. In this review, we summarize recent advances in the development of small molecules that restore the function of mutant p53 by different mechanisms, including stabilization of its folding by Apr-246, which is currently being tested in a Phase II clinical trial. We discuss several classes of compounds that reactivate wild-type p53, such as Mdm2 inhibitors, which are currently undergoing clinical testing, MdmX inhibitors and molecules targeting factors upstream of Mdm2/X or p53 itself. Finally, we consider the clinical applications of compounds targeting p53 and the p53 pathway.
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Zawacka-Pankau
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: G
authors.initials: G
authors.lastname: Selivanova
mesh_terms: D000483:Alleles; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017322:Clinical Trials, Phase II as Topic; D019317:Evidence-Based Medicine; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy / Q000379:methods*; D020125:Mutation, Missense; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2
keywords: anticancer therapy; p53; targeted drugs; transcription factor; tumour suppression