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Identification of small molecule inhibitors of Jumonji AT-rich interactive domain 1B (JARID1B) histone demethylase by a sensitive high throughput screen.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2013 Mar 29; Vol. 288 (13), pp. 9408-17. Date of Electronic Publication: 2013 Feb 13. - Publication Year :
- 2013
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Abstract
- JARID1B (also known as KDM5B or PLU1) is a member of the JARID1 family of histone lysine demethylases responsible for the demethylation of trimethylated lysine 27 in histone H3 (H3K4me3), a mark for actively transcribed genes. JARID1B is overexpressed in several cancers, including breast cancer, prostate cancer, and lung cancer. In addition, JARID1B is required for mammary tumor formation in syngeneic or xenograft mouse models. JARID1B-expressing melanoma cells are associated with increased self-renewal character. Therefore, JARID1B represents an attractive target for cancer therapy. Here we characterized JARID1B using a homogeneous luminescence-based demethylase assay. We then conducted a high throughput screen of over 15,000 small molecules to identify inhibitors of JARID1B. From this screen, we identified several known JmjC histone demethylase inhibitors, including 2,4-pyridinedicarboxylic acid and catechols. More importantly, we identified several novel inhibitors, including 2-4(4-methylphenyl)-1,2-benzisothiazol-3(2H)-one (PBIT), which inhibits JARID1B with an IC50 of about 3 μm in vitro. Consistent with this, PBIT treatment inhibited removal of H3K4me3 by JARID1B in cells. Furthermore, this compound inhibited proliferation of cells expressing higher levels of JARID1B. These results suggest that this novel small molecule inhibitor is a lead compound that can be further optimized for cancer therapy.
- Subjects :
- Animals
Antineoplastic Agents pharmacology
Cell Line
Cell Line, Tumor
Cell Proliferation
Chemistry, Pharmaceutical methods
Drug Design
Epigenesis, Genetic
Histone Demethylases metabolism
Histones chemistry
Humans
Insecta
Neoplasms drug therapy
Peptides chemistry
Protein Binding
Recombinant Proteins chemistry
Thiazoles chemistry
High-Throughput Screening Assays methods
Jumonji Domain-Containing Histone Demethylases antagonists & inhibitors
Jumonji Domain-Containing Histone Demethylases chemistry
Nuclear Proteins antagonists & inhibitors
Nuclear Proteins chemistry
Repressor Proteins antagonists & inhibitors
Repressor Proteins chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 288
- Issue :
- 13
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 23408432
- Full Text :
- https://doi.org/10.1074/jbc.M112.419861