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• W2004261697 abstract "A robust p53 cell based assay that exploits p53's function as a transcription factor was used to screen a small molecule library and identify bioactive small molecules with potential antitumor activity. Unexpectedly, the majority of the highest ranking hit compounds from this screen arrest cells in mitosis and most of them impair polymerisation of tubulin in cells and in vitro. One of these novel compounds, JJ78:1, was subjected to structure-activity relationship studies and optimised leading to the identification of JJ78:12. This molecule is significantly more potent than the original hit JJ78:1, as it is active in cells at two-digit nanomolar concentrations and shows clear antitumor activity in a mouse xenograft model as a single agent. The effects of nocodazole, a well established tubulin poison, and JJ78:12 on p53 levels are remarkably similar, supporting that tubulin depolymerisation is the main mechanism by which JJ78:12 treatment leads to p53 activation in cells. In summary, these results identify JJ78:12 as a potential cancer therapeutic, demonstrate that screening for activators of p53 in a cell-based assay is an effective way to identify inhibitors of mitosis progression and highlights p53's sensitivity to alterations during mitosis." @default.
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• W2004261697 date "2008-11-01" @default.
• W2004261697 modified "2023-09-27" @default.
• W2004261697 title "Characterization, chemical optimization and anti-tumor activity of a tubulin poison identified by a p53-based phenotypic screen" @default.
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• W2004261697 doi "https://doi.org/10.4161/cc.7.21.6982" @default.
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