Design and Optimization of Novel Hydroxamate-Based Histone Deacetylase Inhibitors of Bis-Substituted Aromatic Amides Bearing Potent Activities against Tumor Growth and Metastasis

• Published in: Journal of medicinal chemistry Vol. 57; no. 22; pp. 9357 - 9369
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 26.11.2014; Amer Chemical Soc
• Subjects: Acetylation; Amides - chemistry; Animals; Breast Neoplasms - drug therapy; Cell Line, Tumor; Cell Movement; Cell Proliferation; Chemistry, Medicinal; Drug Design; Female; Histone Deacetylase Inhibitors - chemistry; Humans; Hydroxamic Acids - chemistry; Inhibitory Concentration 50; Life Sciences & Biomedicine; Mice; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms - drug therapy; Pharmacology & Pharmacy; Science & Technology; Xenograft Model Antitumor Assays; CELLS; PAXILLIN; INVASION; THERAPY; ACETYLATION; BIOLOGICAL EVALUATION; CANCER; EXPRESSION; DISCOVERY
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm5012148

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.