+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

Identification of novel small-molecule histone deacetylase inhibitors by medium-throughput screening using a fluorigenic assay



Identification of novel small-molecule histone deacetylase inhibitors by medium-throughput screening using a fluorigenic assay



Biochemical Journal 413(1): 143-150



HDACs (histone deacetylases) are considered to be among the most important enzymes that regulate gene expression in eukaryotic cells. In general, increased levels of histone acetylation are associated with increased transcriptional activity, whereas decreased levels are linked to repression of gene expression. HDACs associate with a number of cellular oncogenes and tumour-suppressor genes, leading to an aberrant recruitment of HDAC activity, which results in changes of gene expression, impaired differentiation and excessive proliferation of tumour cells. Therefore HDAC inhibitors are efficient anti-proliferative agents in both in vitro and in vivo pre-clinical models of cancer, making them promising anticancer therapeutics. In the present paper, we present the results of a medium-throughput screening programme aiming at the identification of novel HDAC inhibitors using HDAH (HDAC-like amidohydrolase) from Bordetella or Alcaligenes strain FB188 as a model enzyme. Within a library of 3719 compounds, several new classes of HDAC inhibitor were identified. Among these hit compounds, there were also potent inhibitors of eukaryotic HDACs, as demonstrated by an increase in histone H4 acetylation, accompanied by a decrease in tumour cell metabolism in both SHEP neuroblastoma and T24 bladder carcinoma cells. In conclusion, screening of a compound library using FB188 HDAH as model enzyme identified several promising new lead structures for further development.

Please choose payment method:






(PDF emailed within 0-6 h: $19.90)

Accession: 053669053

Download citation: RISBibTeXText

PMID: 18384290

DOI: 10.1042/bj20080536


Related references

High-throughput screening for identification of small molecule inhibitors of histone acetyltransferases using scintillating microplates (FlashPlate). Analytical Biochemistry 298(1): 62-68, 2001

A high throughput screening assay system for the identification of small molecule inhibitors of gsp. Plos one 9(3): E90766, 2014

High-throughput screening assay for identification of small molecule inhibitors of Aurora2/STK15 kinase. Journal of Biomolecular Screening 9(5): 391-397, 2004

An in-line capillary electrophoresis assay for the high-throughput screening of histone deacetylase inhibitors. Journal of Chromatography. a 1591: 171-177, 2019

High-throughput screening AlphaScreen assay for identification of small-molecule inhibitors of ubiquitin E3 ligase SCFSkp2-Cks1. Journal of Biomolecular Screening 18(8): 910-920, 2013

Identification of novel small-molecule inhibitors for human transketolase by high-throughput screening with fluorescent intensity (FLINT) assay. Journal of Biomolecular Screening 9(5): 427-433, 2004

Profiling technologies for the identification and characterization of small-molecule histone deacetylase inhibitors. Drug Discovery Today. Technologies 18: 24-28, 2015

Identification and characterization of small molecule inhibitors of a class I histone deacetylase from Plasmodium falciparum. Journal of Medicinal Chemistry 52(8): 2185-2187, 2009

Identification of small molecule inhibitors of the mitotic kinase haspin by high-throughput screening using a homogeneous time-resolved fluorescence resonance energy transfer assay. Journal of Biomolecular Screening 13(10): 1025-1034, 2008

Development of a high-throughput screening assay for the discovery of small-molecule SecA inhibitors. Analytical Biochemistry 413(2): 90-96, 2011

High-throughput screening with nucleosome substrate identifies small-molecule inhibitors of the human histone lysine methyltransferase NSD2. Journal of Biological Chemistry 293(35): 13750-13765, 2018

A three-fluorophore FRET assay for high-throughput screening of small-molecule inhibitors of ribosome assembly. Nucleic Acids Research 32(9): 2707-2715, 2004

A cell-based high-throughput assay for the screening of small-molecule inhibitors of p53-MDM2 interaction. Journal of Biomolecular Screening 16(4): 450-456, 2011

Identification of small molecule inhibitors of p27Kip1 ubiquitination by high-throughput screening. 2013

Identification of small molecule inhibitors of p27(Kip1) ubiquitination by high-throughput screening. Cancer Science 104(11): 1461-1467, 2013