title: Targeting the nucleolus for cancer-specific activation of p53.
abstract: The tumor suppressor protein p53 plays a crucial part in the cellular defense against malignancies. DNA-damaging chemotherapeutics rely on the activation of p53 for their anticancer activity at the expense of genotoxicity. Nongenotoxic approaches for p53 activation have been extensively investigated validating p53 as a therapeutic target. However, their development has been hampered by low efficacy and a narrow therapeutic window. An alternate nongenotoxic approach for cancer-specific activation of wild-type p53 has been recently identified. It relies on the activation of a cellular checkpoint mechanism termed 'nucleolar stress', which can be triggered by acute inhibition of rRNA biogenesis. CX5461, the first selective inhibitor of rRNA biogenesis, and thus a potent activator of nucleolar stress, is poised to enter clinical development.
authors.affiliation: Cylene Pharmaceuticals, 5935 Cornerstone Court West #100, San Diego, CA 92121, USA.
authors.forename: Denis
authors.initials: D
authors.lastname: Drygin
authors.affiliation: Senhwa Bioscience, 9191 Towne Centre Drive, San Diego, CA 92122, USA.
authors.forename: Sean E
authors.initials: SE
authors.lastname: O'Brien
authors.affiliation: Division of Cancer Research, Peter MacCallum Cancer Centre, Locked Bag 1, Melbourne, 8006 Victoria, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3010 Victoria, Australia; Department of Biochemistry and Cell Biology, The University of Melbourne, Parkville, 3010 Victoria, Australia.
authors.forename: Ross D
authors.initials: RD
authors.lastname: Hannan
authors.affiliation: Division of Cancer Research, Peter MacCallum Cancer Centre, Locked Bag 1, Melbourne, 8006 Victoria, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3010 Victoria, Australia.
authors.forename: Grant A
authors.initials: GA
authors.lastname: McArthur
authors.affiliation: The Translational Genomics Research Institute, 445 N. Fifth Street, Phoenix, AZ 85004, USA. Electronic address: dvh@tgen.org.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Von Hoff
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology*; D052160:Benzothiazoles / Q000494:pharmacology; D002466:Cell Nucleolus / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D015195:Drug Design; D006801:Humans; D058990:Molecular Targeted Therapy; D009287:Naphthyridines / Q000494:pharmacology; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D012335:RNA, Ribosomal / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D052160:Benzothiazoles; C557717:CX 5461; D009287:Naphthyridines; D012335:RNA, Ribosomal; D016159:Tumor Suppressor Protein p53