化学
体内
组蛋白脱乙酰基酶
癌症研究
体外
黑色素瘤
乙酰化
免疫系统
DNA
组蛋白
药理学
生物化学
免疫学
生物
基因
生物技术
作者
Chen Chen,Xue Li,Huajun Zhao,Meng Li,Jintong Du,Jian Zhang,Yang Xia,Xuben Hou,Hao Fang
标识
DOI:10.1021/acs.jmedchem.1c02225
摘要
We observed a synergistic antiproliferation effect with combined use of a DNA minor groove binder and a histone deacetylase (HDAC) inhibitor. Inspired by this result, a new series of benzimidazole-hydroxamate hybrids were designed and synthesized to target both DNA minor groove and HDAC. The most active compounds 9k and 9l not only exhibited improved HDAC inhibitory activities compared to SAHA but also possessed potent antiproliferation activities against tumor cells. Importantly, compounds 9k and 9l showed good in vivo antitumor efficacies in both HEL xenograft model and murine melanoma model. We also found that 9k and 9l promote the antigen presentation and activate T cells, thereby triggering antitumor immunity. Moreover, these inhibitors reshaped the tumor immune microenvironment by inhibiting the recruitment of Treg cells and promoting the polarization of tumor-infiltrating macrophages to M2 type with antitumor activity. Our study validated the effectiveness of incorporating a DNA-binding fragment in HDAC inhibitors as novel multitargeting antitumor agents.
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