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

• Published in: Journal of medicinal chemistry Vol. 58; no. 23; pp. 9309 - 9333
• Main Authors: Colley, Helen E, Muthana, Munitta, Danson, Sarah J, Jackson, Lucinda V, Brett, Matthew L, Harrison, Joanne, Coole, Sean F, Mason, Daniel P, Jennings, Luke R, Wong, Melanie, Tulasi, Vamshi, Norman, Dennis, Lockey, Peter M, Williams, Lynne, Dossetter, Alexander G, Griffen, Edward J, Thompson, Mark J
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 10.12.2015; Amer Chemical Soc
• Subjects: Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - therapeutic use; Caco-2 Cells; Cell Proliferation - drug effects; Chemistry, Medicinal; Drug Screening Assays, Antitumor; Head and Neck Neoplasms - drug therapy; Head and Neck Neoplasms - metabolism; Head and Neck Neoplasms - pathology; Heterografts; Humans; Indoles - chemistry; Indoles - pharmacokinetics; Indoles - therapeutic use; Life Sciences & Biomedicine; Male; Mice; Mice, Nude; Microtubules - drug effects; Microtubules - metabolism; Microtubules - pathology; Neoplasm Transplantation; Pharmacology & Pharmacy; Science & Technology; Structure-Activity Relationship; Tubulin - metabolism; Tubulin - ultrastructure; Tubulin Modulators - chemistry; Tubulin Modulators - pharmacokinetics; Tubulin Modulators - therapeutic use; ADMINISTERED INDIBULIN D-24851; LUNG-CANCER; METASTATIC BREAST-CANCER; MATCHED MOLECULAR PAIRS; SQUAMOUS-CELL CARCINOMA; PHASE-II; ERIBULIN MESYLATE; MULTIDRUG-RESISTANCE; MICROTUBULE-TARGETING AGENTS; AQUEOUS SOLUBILITY
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.5b01312

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.