Characterization, chemical optimization and anti-tumour activity of a tubulin poison identified by a p53-based phenotypic screen

Oliver D. Staples, Jonathan J. Hollick, Johanna Campbell, Maureen Higgins, Anna R. McCarthy, Virginia Appleyard, Karen E. Murray, Lee Baker, Alastair Thompson, Sebastien Ronseaux, Alexandra M. Z. Slawin, David P. Lane, Nicholas J. Westwood, Sonia Lain

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    12 Citations (Scopus)

    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 polymerization of tubulin in cells and in vitro. One of these novel compounds, JJ78:1, was subjected to structure-activity relationship studies and optimized 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 depolymerization 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.

    Original languageEnglish
    Pages (from-to)3417-3427
    Number of pages11
    JournalCell Cycle
    Volume7
    Issue number21
    Publication statusPublished - 1 Nov 2008

    Keywords

    • p53
    • tubulin polymerization
    • small molecule screen
    • SMALL MOLECULES
    • IN-VIVO
    • PROLONGED MITOSIS
    • HUMAN TUMORS
    • HUMAN P53
    • PHOSPHORYLATION
    • CELLS
    • DERIVATIVES
    • ACTIVATION
    • INHIBITOR

    Cite this

    Staples, O. D., Hollick, J. J., Campbell, J., Higgins, M., McCarthy, A. R., Appleyard, V., Murray, K. E., Baker, L., Thompson, A., Ronseaux, S., Slawin, A. M. Z., Lane, D. P., Westwood, N. J., & Lain, S. (2008). Characterization, chemical optimization and anti-tumour activity of a tubulin poison identified by a p53-based phenotypic screen. Cell Cycle, 7(21), 3417-3427.