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
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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DOI：
10.1021/acs.jmedchem.5b01312
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发表时间：
2015-12-10
影响因子：
7.3
通讯作者：
Thompson, Mark J.
中科院分区：
文献类型：
--
作者：
Colley, Helen E.;Muthana, Munitta;Thompson, Mark J.
此前已有多种吲哚-3-乙醛酰胺被报道为微管蛋白聚合抑制剂，但尚未在临床上成功开发。我们在这里报告了一系列新的相关化合物，根据减少芳环数量和引入更大程度的饱和度的策略进行修改，它们保留了有效的微管蛋白聚合活性，但具有与先前记录的文库不同的 SAR。报道的系列活性化合物的一个子集显示出与秋水仙碱结合位点的微管蛋白相互作用，破坏细胞微管网络，并对多种癌细胞系发挥细胞毒性作用。两种化合物在小鼠头颈癌异种移植模型中表现出显着的肿瘤生长抑制作用，这种疾病通常对化疗具有抗药性，支持当前系列作为潜在新疗法的进一步开发。
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.