School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, PR China.
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West, Sichuan University, Chengdu, 610041, China.
Eur J Med Chem. 2022 Aug 5;238:114484. doi: 10.1016/j.ejmech.2022.114484. Epub 2022 May 27.
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.
TRAIL 促凋亡途径的激活可以促进癌细胞凋亡。组蛋白去乙酰化酶 (HDACs) 也是癌症有前途的药物靶点，它们与 TRAIL 的协同作用可以提高对癌细胞的抑制作用。因此，开发高度敏感的 TRAIL 的 HDAC 抑制剂可能是治疗癌症的一种有前途的策略。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。化合物 IIc 对 HDAC1 和 HCT116 细胞表现出良好的抑制活性，与 ONC201 相比，它对 TRAIL 蛋白表达的激活和促进 HCT-116 细胞凋亡表现出更高的敏感性。化合物 IIc（25mg/kg）在 HCT-116 异种移植模型中的抑制活性明显大于阳性对照药物（ONC201、西达本胺）。这些发现表明，开发高度敏感的 TRAIL 的 HDAC 抑制剂作为结直肠肿瘤癌症药物。
