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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| Abstract |
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, 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.
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| Authors | 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 |
| Journal | Journal of medicinal chemistry (J Med Chem) Vol. 57 Issue 22 Pg. 9357-69 (Nov 26 2014) ISSN: 1520-4804 [Electronic] United States |
| PMID | 25360834 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
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