Application of p21 and klf2 reporter gene assays to identify selective histone deacetylase inhibitors for cancer therapy

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• 作者：Jason C. Wong ; Lei Guo ; Zhenghong Peng ; Weixing Zhang ; Nan Zhang ; Wayne Lai ; Zhenshan Zhang ; Chao Zhang ; Xiongwen Zhang ; Shan Song ; Desi Pan ; Chuanming Xie ; Jia Li ; Zhiqing Ning ; Xianping Lu ; Yun He
• 关键词：Histone deacetylase ; Histone deacetylase inhibitor ; In-cell selectivity ; Reporter gene assay
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2011
• 出版时间：1 January 2011
• 年：2011
• 卷：21
• 期：1
• 页码：110-116
• 全文大小：2756 K

文摘

Novel 2-aminoanilide histone deacetylase (HDAC) inhibitors were designed to increase their contact with surface residues surrounding the HDAC active site compared to the contacts made by existing clinical 2-aminoanilides such as SNDX-275, MGCD0103, and Chidamide. Their HDAC selectivity was assessed using p21 and klf2 reporter gene assays in HeLa and A204 cells, respectively, which provide a cell-based readout for the inhibition of HDACs associated either with the p21 or klf2 promoter. A subset of the designed compounds selectively induced p21 over klf2 relative to the clinical reference compound SNDX-275. A representative lead compound from this subset had antiproliferative effects in cancer cells associated with induction of acetylated histone H4, endogenous p21, cell cycle arrest, and apoptosis. The p21- versus klf2-selective compounds described herein may provide a chemical starting point for developing clinically-differentiated HDAC inhibitors for cancer therapy.