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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• 作者：Helen E. Colley ; Munitta Muthana ; Sarah J. Danson ; Lucinda V. Jackson ; Matthew L. Brett ; Joanne Harrison ; Sean F. Coole ; Daniel P. Mason ; Luke R. Jennings ; Melanie Wong ; Vamshi Tulasi ; Dennis Norman ; Peter M. Lockey ; Lynne Williams ; Alexander G. Dossetter ; Edward J. Griffen ; Mark J. Thompson
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：December 10, 2015
• 年：2015
• 卷：58
• 期：23
• 页码：9309-9333
• 全文大小：1163K
• ISSN：1520-4804

文摘

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.