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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• 作者：Feifei Yang ; Tao Zhang ; Haigang Wu ; Yang Yang ; Ning Liu ; Ang Chen ; Qiang Li ; Jingjie Li ; Liwen Qin ; Beier Jiang ; Xin Wang ; Xiufeng Pang ; Zhengfang Yi ; Mingyao Liu ; Yihua Chen
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：November 26, 2014
• 年：2014
• 卷：57
• 期：22
• 页码：9357-9369
• 全文大小：641K
• ISSN：1520-4804

文摘

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鈥揳ctivity relationship. Among them, compound 11b, one of the most potent leads, exhibited nanomolar IC₅₀ values 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.