title: Design and optimization of novel hydroxamate-based histone deacetylase inhibitors of Bis-substituted aromatic amides bearing potent activities against tumor growth and metastasis.
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.
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences and School of Life Sciences, East China Normal University , Shanghai, 200241, China.
authors.forename: Feifei
authors.initials: F
authors.lastname: Yang
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.forename: Haigang
authors.initials: H
authors.lastname: Wu
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.forename: Ning
authors.initials: N
authors.lastname: Liu
authors.forename: Ang
authors.initials: A
authors.lastname: Chen
authors.forename: Qiang
authors.initials: Q
authors.lastname: Li
authors.forename: Jingjie
authors.initials: J
authors.lastname: Li
authors.forename: Liwen
authors.initials: L
authors.lastname: Qin
authors.forename: Beier
authors.initials: B
authors.lastname: Jiang
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Xiufeng
authors.initials: X
authors.lastname: Pang
authors.forename: Zhengfang
authors.initials: Z
authors.lastname: Yi
authors.forename: Mingyao
authors.initials: M
authors.lastname: Liu
authors.forename: Yihua
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000107:Acetylation; D000577:Amides / Q000737:chemistry*; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D015195:Drug Design; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry*; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry; D020128:Inhibitory Concentration 50; D051379:Mice; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000577:Amides; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids