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

Targeting the nucleolus for cancer-specific activation of p53.

Author information

1
Cylene Pharmaceuticals, 5935 Cornerstone Court West #100, San Diego, CA 92121, USA.
2
Senhwa Bioscience, 9191 Towne Centre Drive, San Diego, CA 92122, USA.
3
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.
4
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.
5
The Translational Genomics Research Institute, 445 N. Fifth Street, Phoenix, AZ 85004, USA. Electronic address: dvh@tgen.org.

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.

PMID:
23993916
DOI:
10.1016/j.drudis.2013.08.012
[Indexed for MEDLINE]

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