Hydroxamate-Based Histone Deacetylase Inhibitors of Bis-Substituted Aromatic Amides Bearing Potent Activities against Tumor Growth and Metastasis
Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China
J. Med. Chem., 2014, 57 (22), pp 9357–9369
DOI: 10.1021/jm5012148
Publication Date (Web): October 31, 2014
Copyright © 2014 American Chemical Society
*Y.C.: phone, +86-21-2420-6647; fax, +86-21-54344922; e-mail, yhchen@bio.ecnu.edu.cn., *M.L.: phone, +86-21-5434-5124; fax, +86-21-54344922; e-mail, myliu@bio.ecnu.edu.cn., *Z.Y.: phone, +86-21-5434-5016; fax, +86-21-54344922; e-mail, zfyi@bio.ecnu.edu.cn.
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.
Supporting Information
Detailed docking studies of selected compounds with HDAC2 and -8. Additional details of the procedures used for the in vitro and in vivo related biological studies as well as pharmacokinetic studies. This material is available free of charge via the Internet at http://pubs.acs.org.
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