血管破壊活性とEHT 6706の作用メカニズム、新規の抗がんチューブリン重合阻害剤

腫瘍血管は、抗がん療法の重要な新興標的です。Here, we characterize the in vitro antiproliferative and antiangiogenic properties of the synthetic small molecule, 7-ethoxy-4-(3,4,5-trimethoxybenzyl)isoquinolin-8-amine dihydrochloride, EHT 6706, a novel microtubule-disrupting agent that targets the colchicine-binding site to inhibit tubulin重合。NM濃度が低い場合、EHT 6706は、60を超えるヒト腫瘍細胞株で非常に強力な抗増殖活性を示します。EHT 6706は、内皮細胞チューブの形成を防ぎ、事前に確立された血管を破壊し、内皮細胞単層の透過性を変化させ、内皮細胞の移動を阻害するため、血管破壊剤としての強力な有効性を示します。ヒト内皮細胞に対するEHT 6706の効果のゲノムワイドトランスクリプトーム分析は、抗血管新生活性が抗血管新生経路の遺伝子規制を誘発することを示しています。これらの発見は、EHT 6706が潜在的に広範な臨床抗腫瘍効果を伴う有望なチューブリン結合化合物であることを示しています。

Tumor blood vessels are an important emerging target for anticancer therapy. Here, we characterize the in vitro antiproliferative and antiangiogenic properties of the synthetic small molecule, 7-ethoxy-4-(3,4,5-trimethoxybenzyl)isoquinolin-8-amine dihydrochloride, EHT 6706, a novel microtubule-disrupting agent that targets the colchicine-binding site to inhibit tubulin polymerization. At low nM concentrations, EHT 6706 exhibits highly potent antiproliferative activity on more than 60 human tumor cell lines, even those described as being drug resistant. EHT 6706 also shows strong efficacy as a vascular-disrupting agent, since it prevents endothelial cell tube formation and disrupts pre-established vessels, changes the permeability of endothelial cell monolayers and inhibits endothelial cell migration. Genome-wide transcriptomic analysis of EHT 6706 effects on human endothelial cells shows that the antiangiogenic activity elicits gene deregulations of antiangiogenic pathways. These findings indicate that EHT 6706 is a promising tubulin-binding compound with potentially broad clinical antitumor efficacy.