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.
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