Transforming acidic coiled coil containing protein 3 (TACC3) is emerging as an attractive anticancer target in recent years, however, few TACC3 small-molecular inhibitors have been reported up to now. In this study, fifteen compounds were designed and synthesized based on the lead compound KHS101 to find more potent TACC3 inhibitors. Among them, the most potent compound 7g exhibited about 10-folds more potent antiproliferative activities than KHS101 in various cancer cell lines. Two different protein-drug binding assays including DARTS, and CETSA revealed TACC3 as a biologically relevant target of compound 7g. In addition, compound 7g induced cell cycle arrest at the G2/M phase and induced cell apoptosis. Furthermore, compound 7g depolarized the MMP and induced ROS generation in a dose-dependent manner in U87 cells. More importantly, 7g reduced tumor weight by 72.7% in U87 xenograft model at a dose of 20 mg/kg/day without obvious toxicity. Altogether, compound 7g deserved further investigations as a novel, safe and efficacious TACC3 inhibitor for the treatment of GBM.

转化酸性卷曲螺旋蛋白 3 (TACC3) 近年来逐渐成为一个有吸引力的抗癌靶点，然而，迄今为止，很少有 TACC3 小分子抑制剂的报道。在这项研究中，基于先导化合物 KHS101 设计并合成了 15 种化合物，以寻找更有效的 TACC3 抑制剂。其中，最有效的化合物7g在各种癌细胞系中表现出比 KHS101 强约 10 倍的抗增殖活性。包括 DARTS 和 CETSA 在内的两种不同的蛋白质-药物结合测定显示 TACC3 是化合物7g的生物学相关靶标。此外，化合物7g诱导细胞周期停滞在G2/M期并诱导细胞凋亡。此外，化合物7g在 U87 细胞中以剂量依赖性方式去极化 MMP 并诱导 ROS 生成。更重要的是，7g在 U87 异种移植模型中以 20 mg/kg/day 的剂量使肿瘤重量减少了 72.7%，并且没有明显的毒性。总之，化合物7g作为治疗 GBM 的新型、安全和有效的 TACC3 抑制剂值得进一步研究。