Loading...
Please wait, while we are loading the content...
Similar Documents
Identification of novel small-molecule histone deacetylase inhibitors by medium-throughput screening using a fluorogenic assay
| Content Provider | Hyper Articles en Ligne (HAL) |
|---|---|
| Author | Wegener, Dennis Hildmann, Christian Riester, Daniel Schober, Andreas Meyer-Almes, Franz-Josef Deubzer, Hedwig Oehme, Ina Witt, Olaf Lang, Siegmund Jaensch, Martina Makarov, Vadim Lange, Corinna Busse, Benedikt Schwienhorst, Andreas |
| Abstract | Histone deacetylases (HDACs) are considered to be among the most important enzymes regulating 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 tumor-suppressor genes leading to an aberrant recruitment of HDAC activity, which results in changes of gene expression, impaired differentiation and excessive proliferation of tumor cells. Therefore, HDAC-inhibitors are efficient anti-proliferative agents in both in vitro and in vivo preclinical models of cancer making them promising anti-cancer therapeutics. Here, we present the results of a medium-throughput screening program aiming at the identification of novel HDAC-inhibitors using histone deacetylase-like amidohydrolase from strain FB188 (FB188 HDAH) as model enzyme. Within a library of 3719 compounds, several new classes of HDAC-inhibitors 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 tumor 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. |
| Ending Page | 150 |
| Page Count | 8 |
| Starting Page | 143 |
| File Format | |
| ISSN | 02646021 |
| e-ISSN | 14708728 |
| DOI | 10.1042/BJ20080536 |
| Journal | Biochemical Journal |
| Issue Number | 1 |
| Volume Number | 413 |
| Language | English |
| Publisher | Portland Press |
| Publisher Date | 2008-06-12 |
| Access Restriction | Open |
| Subject Keyword | Life Sciences |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Molecular Biology Biochemistry |
