An Orally Bioavailable, Indole-3-glyoxylamide Based Series of Tubulin Polymerization Inhibitors Showing Tumor Growth Inhibition in a Mouse Xenograft Model of Head and Neck Cancer.

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Colley, H.E. ; Muthana, M. ; Danson, S.J. ; Jackson, L.V. ; Brett, M.L. ; Harrison, J. ; Coole, S.F. ; Mason, D.P. ; Jennings, L.R. ; Wong, M. ; Tulasi, V. ; Norman, D. ; Lockey, P.M. ; Williams, L. ; Dossetter, A.G. ; Griffen, E.J. ; Thompson, M.J. (2015)
  • Publisher: American Chemical Society

A number of indole-3-glyoxylamides have previously been reported as tubulin polymerization inhibitors, although none has yet been successfully developed clinically. We report here a new series of related compounds, modified according to a strategy of reducing aromatic ring count and introducing a greater degree of saturation, which retain potent tubulin polymerization activity but with a distinct SAR from previously documented libraries. A subset of active compounds from the reported series is shown to interact with tubulin at the colchicine binding site, disrupt the cellular microtubule network, and exert a cytotoxic effect against multiple cancer cell lines. Two compounds demonstrated significant tumor growth inhibition in a mouse xenograft model of head and neck cancer, a type of the disease which often proves resistant to chemotherapy, supporting further development of the current series as potential new therapeutics.
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