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

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.