Activation of the TRAIL proapoptotic pathway can promote cancer cell apoptosis. Histone deacetylases (HDACs) also are promising drug targets for cancers, and their synergistic effect with TRAIL can improve the inhibitory effect on cancer cells. Therefore, the development of highly TRAIL-sensitive HDAC inhibitors might be a promising strategy for the treatment of cancers. We synthesized a series of HDAC inhibitors by introducing effective fragments sensitive to TRAIL. Compound IIc showed good inhibitory activity against HDAC1 and HCT116 cells and showed higher sensitivity to activating the expression of the TRAIL protein and promoting the apoptosis of HCT-116 cells compared with ONC201. The inhibitory activity of compound IIc (25 mg/kg) in the HCT-116 xenograft model was significantly greater than those of the positive control drugs (ONC201, chidamide). These findings suggested that development of highly TRAIL-sensitive HDAC inhibitors as colorectal tumor cancer drugs.

激活 TRAIL 促凋亡通路可促进癌细胞凋亡。组蛋白去乙酰化酶（HDACs）也是很有前景的癌症药物靶点，其与TRAIL的协同作用可以提高对癌细胞的抑制作用。因此，开发对 TRAIL 高度敏感的 HDAC 抑制剂可能是治疗癌症的有希望的策略。我们通过引入对TRAIL敏感的有效片段合成了一系列HDAC抑制剂。与ONC201相比，化合物IIc对HDAC1和HCT116细胞具有良好的抑制活性，对激活TRAIL蛋白表达和促进HCT-116细胞凋亡的敏感性更高。化合物IIc的抑制活性在 HCT-116 异种移植模型中 (25 mg/kg) 显着高于阳性对照药物 (ONC201, chidamide)。这些发现表明高度敏感的HDAC抑制剂可作为结直肠肿瘤药物的开发。