Targeting the nucleolus for cancer-specific activation of p53

Drug Discov Today. 2014 Mar;19(3):259-65. doi: 10.1016/j.drudis.2013.08.012. Epub 2013 Aug 28.


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.

Publication types

  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / pharmacology*
  • Benzothiazoles / pharmacology
  • Cell Nucleolus / metabolism
  • DNA Damage / drug effects
  • Drug Design
  • Humans
  • Molecular Targeted Therapy
  • Naphthyridines / pharmacology
  • Neoplasms / drug therapy*
  • Neoplasms / pathology
  • RNA, Ribosomal / metabolism
  • Tumor Suppressor Protein p53 / metabolism*


  • Antineoplastic Agents
  • Benzothiazoles
  • CX 5461
  • Naphthyridines
  • RNA, Ribosomal
  • Tumor Suppressor Protein p53