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.

Article English OPEN
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.
  • References (142)
    142 references, page 1 of 15

    (1) Nitika, V.; Kapil, K. Microtubule targeting agents: a benchmark in cancer therapy. Curr. Drug Ther. 2014, 8, 189−196.

    (2) Risinger, A. L.; Giles, F. J.; Mooberry, S. L. Microtubule dynamics as a target in oncology. Cancer Treat. Rev. 2009, 35, 255−261.

    (3) Stanton, R. A.; Gernert, K. M.; Nettles, J. H.; Aneja, R. Drugs that target dynamic microtubules: a new molecular perspective. Med. Res.

    Rev. 2011, 31, 443−481.

    (4) Barbier, P.; Tsvetkov, P. O.; Breuzard, G.; Devred, F. Deciphering the molecular mechanisms of anti-tubulin plant derived drugs.

    Phytochem. Rev. 2014, 13, 157−169.

    (5) Rohena, C. C.; Mooberry, S. L. Recent progress with microtubule stabilizers: new compounds, binding modes and cellular activities. Nat.

    Prod. Rep. 2014, 31, 335−355.

    (6) Jordan, M. A.; Horwitz, S. B.; Lobert, S.; Correia, J. J. Exploring the mechanisms of action of the novel microtubule inhibitor vinflunine. Semin. Oncol. 2008, 35, S6−S12.

    (7) Field, J. J.; Kanakkanthara, A.; Miller, J. H. Microtubule-targeting agents are clinically successful due to both mitotic and interphase impairment of microtubule function. Bioorg. Med. Chem. 2014, 22, 5050−5059.

  • Related Research Results (1)
  • Metrics
    0
    views in OpenAIRE
    0
    views in local repository
    17
    downloads in local repository

    The information is available from the following content providers:

    From Number Of Views Number Of Downloads
    White Rose Research Online - IRUS-UK 0 17
Share - Bookmark