1. Design and Optimization ofNovel Hydroxamate-BasedHistone Deacetylase Inhibitors of Bis-Substituted Aromatic AmidesBearing Potent Activities against Tumor Growth and Metastasis.
- Author
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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, and Chen, Yihua
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DRUG design , *HISTONE deacetylase inhibitors , *SUBSTITUENTS (Chemistry) , *TARGETED drug delivery , *CANCER treatment , *ANTINEOPLASTIC agents , *STRUCTURE-activity relationship in pharmacology , *TUMOR growth - Abstract
Histone deacetylases (HDACs) areone of the most promising drugtargets for cancer therapy, and since more than 90% of all cancer-relateddeaths are associated with tumor metastasis, developing strategiesto inhibit tumor metastasis while retaining anti-tumor growth activityare of great interest. Herein we demonstrated the design and identificationof a series of novel hydroxamate-based HDAC inhibitors bearing potentactivities against tumor growth and metastasis. Optimization of theinitial hit resulted in the discovery of new HDAC inhibitors throughstudying the structure–activity relationship. Among them, compound 11b, one of the most potent leads, exhibited nanomolar IC50values toward inhibition of class I and IIb HDACs as wellas sub-micromolar activity against proliferation and migration ofbreast cancer cells in vitro. More importantly, it also significantlysuppressed tumor growth in a breast tumor xenograft mouse model anddose-dependently blocked in vivo tumor metastasis in a mouse pulmonarymetastasis model. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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