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Application of p21 and klf2 reporter gene assays to identify selective histone deacetylase inhibitors for cancer therapy.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2011 Jan 01; Vol. 21 (1), pp. 110-6. Date of Electronic Publication: 2010 Nov 19. - Publication Year :
- 2011
-
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.<br /> (Copyright © 2010 Elsevier Ltd. All rights reserved.)
- Subjects :
- Aminopyridines therapeutic use
Anilides chemical synthesis
Anilides chemistry
Anilides therapeutic use
Antineoplastic Agents chemical synthesis
Antineoplastic Agents therapeutic use
Benzamides therapeutic use
Catalytic Domain
Cell Line, Tumor
Genes, Reporter
Histone Deacetylase Inhibitors chemical synthesis
Histone Deacetylase Inhibitors therapeutic use
Histone Deacetylases metabolism
Humans
Neoplasms drug therapy
Promoter Regions, Genetic
Pyrimidines therapeutic use
Structure-Activity Relationship
Antineoplastic Agents chemistry
Cyclin-Dependent Kinase Inhibitor p21 genetics
Histone Deacetylase Inhibitors chemistry
Histone Deacetylases chemistry
Kruppel-Like Transcription Factors genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 21
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 21145737
- Full Text :
- https://doi.org/10.1016/j.bmcl.2010.11.063