ABSTRACT
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.
Subject(s)
Antineoplastic Agents , Colorectal Neoplasms , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Apoptosis , Cell Line, Tumor , Colorectal Neoplasms/pathology , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylase Inhibitors/therapeutic use , Humans , Imidazoles , Pyridines , Pyrimidines/pharmacology , TNF-Related Apoptosis-Inducing Ligand/pharmacology , TNF-Related Apoptosis-Inducing Ligand/therapeutic useABSTRACT
Snail and histone deacetylases (HDACs) have an important impact on cancer treatment, especially for their synergy. Therefore, the development of inhibitors targeting both Snail and HDAC might be a promising strategy for the treatment of cancers. In this work, we synthesized a series of Snail/HDAC dual inhibitors. Compound 9n displayed the most potent inhibitory activity against HDAC1 with an IC50 of 0.405 µM, potent inhibition against Snail with a Kd of 0.180 µM, and antiproliferative activity in HCT-116 cell lines with an IC50 of 0.0751 µM. Compound 9n showed a good inhibitory effect on NCI-H522 (GI50 = 0.0488 µM), MDA-MB-435 (GI50 = 0.0361 µM), and MCF7 (GI50 = 0.0518 µM). Docking studies showed that compound 9n can be well docked into the active binding sites of Snail and HDAC. Further studies showed that compound 9n increased histone H4 acetylation in HCT-116 cells and decreased the expression of Snail protein to induce cell apoptosis. These findings highlight the potential for the development of Snail/HDAC dual inhibitors as anti-solid tumour cancer drugs.
