Design and Optimization of Novel Hydroxamate-Based Histone Deacetylase Inhibitors of Bis-Substituted Aromatic Amides Bearing Potent Activities against Tumor Growth and Metastasis
Design and Optimization of Novel Hydroxamate-Based Histone Deacetylase Inhibitors of Bis-Substituted Aromatic Amides Bearing Potent Activities against Tumor Growth and Metastasis
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新型异羟肟酸基双取代芳香酰胺组蛋白脱乙酰酶抑制剂的设计和优化，具有有效的抗肿瘤生长和转移活性
DOI：
10.1021/jm5012148
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发表时间：
2014
影响因子：
7.3
通讯作者：
Chen Yihua
中科院分区：
文献类型：
--
作者：
Yang Feifei;Zhang Tao;Wu Haigang;Yang Yang;Liu Ning;Chen Ang;Li Qiang;Li Jingjie;Qin Liwen;Jiang Beier;Wang Xin;Pang Xiufeng;Yi Zhengfang;Liu Mingyao;Chen Yihua
组蛋白脱乙酰酶（HDAC）是癌症治疗中最有前途的药物靶标之一，并且由于超过90%的所有癌症相关死亡与肿瘤转移相关，因此开发抑制肿瘤转移同时保留抗肿瘤生长活性的策略具有极大的兴趣。在此，我们展示了一系列新的基于异羟肟酸的HDAC抑制剂的设计和鉴定，其具有有效的抗肿瘤生长和转移活性。通过研究结构-活性关系，优化初始命中导致发现新的HDAC抑制剂。其中，化合物11b是最有效的先导化合物之一，在体外表现出抑制I类和IIb类HDAC的纳摩尔IC 50值以及亚微摩尔的抗乳腺癌细胞增殖和迁移活性。更重要的是，它还显著抑制了乳腺肿瘤异种移植小鼠模型中的肿瘤生长，并剂量依赖性地阻断了小鼠肺转移模型中的体内肿瘤转移。
Histone deacetylases (HDACs) are one of the most promising drug targets for cancer therapy, and since more than 90% of all cancer-related deaths are associated with tumor metastasis, developing strategies to inhibit tumor metastasis while retaining anti-tumor growth activity are of great interest. Herein we demonstrated the design and identification of a series of novel hydroxamate-based HDAC inhibitors bearing potent activities against tumor growth and metastasis. Optimization of the initial hit resulted in the discovery of new HDAC inhibitors through studying the structure–activity relationship. Among them, compound11b, one of the most potent leads, exhibited nanomolar IC50values toward inhibition of class I and IIb HDACs as well as sub-micromolar activity against proliferation and migration of breast cancer cells in vitro. More importantly, it also significantly suppressed tumor growth in a breast tumor xenograft mouse model and dose-dependently blocked in vivo tumor metastasis in a mouse pulmonary metastasis model.