title: Reactivation of p53: from peptides to small molecules.
abstract: Approximately 27 million people are living with a tumour in which the tumour suppressing activity of p53 has been inactivated. In half of these tumours, p53 itself is not mutated but the pathway is partially abrogated. Mechanisms include the overexpression of negative regulators of p53, such as MDM2 and MDM4, and deletion or epigenetic inactivation of the positive regulators of p53 such as ARF. In the other half of tumours, in which p53 is inactivated, p53 is mutated and ∼95% of these mutations lie in the core DNA-binding domain, which reflects the key role of p53 as a transcriptional activator. Reactivation of the tumour suppressive properties of p53 is a key therapeutic goal, and the use of peptides in p53 research has led directly to the development of two alternative small molecule approaches: stabilization of mutant p53 to rescue its DNA-binding activity and inhibition of MDM2 or MDM4.
authors.affiliation: p53 Laboratory (p53Lab, A*STAR), 8A Biomedical Grove, #06-06, Immunos, 138648, Singapore.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Brown
authors.forename: Chit F
authors.initials: CF
authors.lastname: Cheok
authors.forename: Chandra S
authors.initials: CS
authors.lastname: Verma
authors.forename: David P
authors.initials: DP
authors.lastname: Lane
mesh_terms: D020727:ADP-Ribosylation Factors / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D018797:Cell Cycle Proteins; D015195:Drug Design; D006801:Humans; D008968:Molecular Conformation; D018716:Molecular Mimicry; D050505:Mutant Proteins / Q000819:agonists; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000819:agonists* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; C482775:MDM4 protein, human; D050505:Mutant Proteins; D009687:Nuclear Proteins; D010455:Peptides; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D044767:Ubiquitin-Protein Ligases; D020727:ADP-Ribosylation Factors