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

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

Research output: Contribution to journal › Article › peer-review

15 Scopus citations

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.

Original language	English
Pages (from-to)	110-116
Number of pages	7
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	21
Issue number	1
DOIs	https://doi.org/10.1016/j.bmcl.2010.11.063
State	Published - 1 Jan 2011
Externally published	Yes

Keywords

Histone deacetylase
Histone deacetylase inhibitor
In-cell selectivity
Reporter gene assay

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.bmcl.2010.11.063

Cite this

Wong, J. C., Guo, L., Peng, Z., Zhang, W., Zhang, N., Lai, W., Zhang, Z., Zhang, C., Zhang, X., Song, S., Pan, D., Xie, C., Li, J., Ning, Z., Lu, X., He, Y., & Chen, L. (2011). Application of p21 and klf2 reporter gene assays to identify selective histone deacetylase inhibitors for cancer therapy. Bioorganic and Medicinal Chemistry Letters, 21(1), 110-116. https://doi.org/10.1016/j.bmcl.2010.11.063

@article{7b20e68f9d70458c822ad568cf19fd77,

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

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.",

keywords = "Histone deacetylase, Histone deacetylase inhibitor, In-cell selectivity, Reporter gene assay",

author = "Wong, \{Jason C.\} and Lei Guo and Zhenghong Peng and Weixing Zhang and Nan Zhang and Wayne Lai and Zhenshan Zhang and Chao Zhang and Xiongwen Zhang and Shan Song and Desi Pan and Chuanming Xie and Jia Li and Zhiqing Ning and Xianping Lu and Yun He and Li Chen",

year = "2011",

month = jan,

day = "1",

doi = "10.1016/j.bmcl.2010.11.063",

language = "英语",

volume = "21",

pages = "110--116",

journal = "Bioorganic and Medicinal Chemistry Letters",

issn = "0960-894X",

publisher = "Elsevier Ltd",

number = "1",

}

Wong, JC, Guo, L, Peng, Z, Zhang, W, Zhang, N, Lai, W, Zhang, Z, Zhang, C, Zhang, X, Song, S, Pan, D, Xie, C, Li, J, Ning, Z, Lu, X, He, Y & Chen, L 2011, 'Application of p21 and klf2 reporter gene assays to identify selective histone deacetylase inhibitors for cancer therapy', Bioorganic and Medicinal Chemistry Letters, vol. 21, no. 1, pp. 110-116. https://doi.org/10.1016/j.bmcl.2010.11.063

TY - JOUR

T1 - Application of p21 and klf2 reporter gene assays to identify selective histone deacetylase inhibitors for cancer therapy

AU - Wong, Jason C.

AU - Guo, Lei

AU - Peng, Zhenghong

AU - Zhang, Weixing

AU - Zhang, Nan

AU - Lai, Wayne

AU - Zhang, Zhenshan

AU - Zhang, Chao

AU - Zhang, Xiongwen

AU - Song, Shan

AU - Pan, Desi

AU - Xie, Chuanming

AU - Li, Jia

AU - Ning, Zhiqing

AU - Lu, Xianping

AU - He, Yun

AU - Chen, Li

PY - 2011/1/1

Y1 - 2011/1/1

N2 - 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.

AB - 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.

KW - Histone deacetylase

KW - Histone deacetylase inhibitor

KW - In-cell selectivity

KW - Reporter gene assay

UR - https://www.scopus.com/pages/publications/78650517288

U2 - 10.1016/j.bmcl.2010.11.063

DO - 10.1016/j.bmcl.2010.11.063

M3 - 文章

C2 - 21145737

AN - SCOPUS:78650517288

SN - 0960-894X

VL - 21

SP - 110

EP - 116

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 1

ER -

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

Abstract

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this