title: Identification of small molecule inhibitors of Jumonji AT-rich interactive domain 1B (JARID1B) histone demethylase by a sensitive high throughput screen.
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.
authors: Department of Pathology, Yale School of Medicine, New Haven, CT 06520, USA.
authors: Joyce
authors: J
authors: Sayegh
authors: Jian
authors: J
authors: Cao
authors: Mike Ran
authors: MR
authors: Zou
authors: Alfonso
authors: A
authors: Morales
authors: Lauren P
authors: LP
authors: Blair
authors: Michael
authors: M
authors: Norcia
authors: Denton
authors: D
authors: Hoyer
authors: Alan J
authors: AJ
authors: Tackett
authors: Jane S
authors: JS
authors: Merkel
authors: Qin
authors: Q
authors: Yan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D044127:Epigenesis, Genetic; D057166:High-Throughput Screening Assays / Q000379:methods*; D056466:Histone Demethylases / Q000378:metabolism; D006657:Histones / Q000737:chemistry; D006801:Humans; D007313:Insecta; D056484:Jumonji Domain-Containing Histone Demethylases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D009369:Neoplasms / Q000188:drug therapy; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D011994:Recombinant Proteins / Q000737:chemistry; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D013844:Thiazoles / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D006657:Histones; D009687:Nuclear Proteins; D010455:Peptides; D011994:Recombinant Proteins; D012097:Repressor Proteins; D013844:Thiazoles; D056466:Histone Demethylases; D056484:Jumonji Domain-Containing Histone Demethylases; C119611:KDM5B protein, human; C015699:1,2-benzisothiazoline-3-one