Design and optimization of novel hydroxamate-based histone deacetylase inhibitors of Bis-substituted aromatic amides bearing potent activities against tumor growth and metastasis

  • J Med Chem. 2014 Nov 26;57(22):9357-69. doi: 10.1021/jm5012148.
Feifei Yang  1 ,  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
Affiliations
  • 1. Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences and School of Life Sciences, East China Normal University , Shanghai, 200241, China.
PMID: 25360834 DOI: 10.1021/jm5012148
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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