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

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; Li Chen

doi:10.1016/j.bmcl.2010.11.063

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

Bioorg Med Chem Lett. 2011 Jan 1;21(1):110-6. doi: 10.1016/j.bmcl.2010.11.063. Epub 2010 Nov 19.

Authors

Jason C Wong¹, 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, Li Chen

Affiliation

¹ Roche R&D Center China Ltd, 720 Cai Lun Road, Building 5, Pudong, Shanghai 201203, PR China. [email protected]

PMID: 21145737
DOI: 10.1016/j.bmcl.2010.11.063

Abstract

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.

MeSH terms

Aminopyridines / therapeutic use
Anilides / chemical synthesis
Anilides / chemistry
Anilides / therapeutic use
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry*
Antineoplastic Agents / therapeutic use
Benzamides / therapeutic use
Catalytic Domain
Cell Line, Tumor
Cyclin-Dependent Kinase Inhibitor p21 / genetics*
Genes, Reporter
Histone Deacetylase Inhibitors / chemical synthesis
Histone Deacetylase Inhibitors / chemistry*
Histone Deacetylase Inhibitors / therapeutic use
Histone Deacetylases / chemistry*
Histone Deacetylases / metabolism
Humans
Kruppel-Like Transcription Factors / genetics*
Neoplasms / drug therapy
Promoter Regions, Genetic
Pyrimidines / therapeutic use
Structure-Activity Relationship

Substances

Aminopyridines
Anilides
Antineoplastic Agents
Benzamides
Cyclin-Dependent Kinase Inhibitor p21
Histone Deacetylase Inhibitors
KLF2 protein, human
Kruppel-Like Transcription Factors
Pyrimidines
N-(2-amino-5-fluorobenzyl)-4-(N-(pyridine-3-acrylyl)aminomethyl)benzamide
mocetinostat
Histone Deacetylases