title: Drugging the p53 pathway: understanding the route to clinical efficacy.
abstract: The tumour suppressor p53 is the most frequently mutated gene in human cancer, with more than half of all human tumours carrying mutations in this particular gene. Intense efforts to develop drugs that could activate or restore the p53 pathway have now reached clinical trials. The first clinical results with inhibitors of MDM2, a negative regulator of p53, have shown efficacy but hint at on-target toxicities. Here, we describe the current state of the development of p53 pathway modulators and new pathway targets that have emerged. The challenge of targeting protein-protein interactions and a fragile mutant transcription factor has stimulated many exciting new approaches to drug discovery.
authors.forename: Kian Hoe
authors.initials: KH
authors.lastname: Khoo
authors.affiliation: p53 Laboratory (p53Lab), Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, #06-06, Immunos, 138648 Singapore.
authors.forename: Khoo Kian
authors.initials: KK
authors.lastname: Hoe
authors.affiliation: 1] Bioinformatics Institute, Agency for Science, Technology and Research (A*STAR), 30 Biopolis Street #07-01, Matrix, 138671 Singapore. [2] School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, 637551 Singapore. [3] Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, 117543 Singapore.
authors.forename: Chandra S
authors.initials: CS
authors.lastname: Verma
authors.affiliation: p53 Laboratory (p53Lab), Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, #06-06, Immunos, 138648 Singapore.
authors.forename: David P
authors.initials: DP
authors.lastname: Lane
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D002986:Clinical Trials as Topic / Q000379:methods; D055808:Drug Discovery / Q000379:methods* / Q000639:trends; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D016159:Tumor Suppressor Protein p53