Potent and Selective KDM5 Inhibitor Stops Cellular Demethylation of H3K4me3 at Transcription Start Sites and Proliferation of MM1S Myeloma Cells.
Potent and Selective KDM5 Inhibitor Stops Cellular Demethylation of H3K4me3 at Transcription Start Sites and Proliferation of MM1S Myeloma Cells.
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DOI：
10.1016/j.chembiol.2017.02.006
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发表时间：
2017-03-16
影响因子：
8.6
通讯作者：
Brennan PE
中科院分区：
文献类型：
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作者：
Tumber A;Nuzzi A;Hookway ES;Hatch SB;Velupillai S;Johansson C;Kawamura A;Savitsky P;Yapp C;Szykowska A;Wu N;Bountra C;Strain-Damerell C;Burgess-Brown NA;Ruda GF;Fedorov O;Munro S;England KS;Nowak RP;Schofield CJ;La Thangue NB;Pawlyn C;Davies F;Morgan G;Athanasou N;Müller S;Oppermann U;Brennan PE
组蛋白尾部赖氨酸残基的甲基化是一种动态的表观遗传修饰，在染色质结构和基因调控中起着关键作用。KDM 5（也称为JARID 1）亚家族的成员是2-酮戊二酸（2-OG）和Fe 2+依赖性加氧酶，其充当组蛋白3赖氨酸4三甲基（H3 K4 me 3）脱甲基酶，调节增殖、干细胞自我更新和分化。在这里，我们提出了KDM 5酶抑制剂KDOAM-25的表征。KDOAM-25在体外对KDM 5A-D显示出生化半最大抑制浓度值<100 nM，对其他2-OG加氧酶亚家族具有高选择性，并且对一组55种受体和酶没有脱靶活性。在人细胞检测系统中，KDOAM-25的半最大有效浓度为1050 μM，对其他脱甲基酶具有良好的选择性。KDM 5 B在多发性骨髓瘤中过表达，与总生存率呈负相关。用KDOAM-25处理的多发性骨髓瘤MM 1 S细胞显示在转录起始位点的整体H3 K4甲基化增加和增殖受损。KDOAM-25是KDM 5A-D的选择性抑制剂，H3 K4 me 3赖氨酸脱甲基酶KDOAM-25在免疫荧光测定中抑制H3 K4 me 3的脱甲基化。KDM 5 B表达增加与多发性骨髓瘤KDOAM-25处理的细胞中生存期缩短相关，显示转录起始位点H3 K4 me 3增加。报道了KDOAM-25的发现和表征，KDOAM-25是KDM 5 H3 K4 me 3赖氨酸脱甲基酶的有效和选择性抑制剂。KDOAM-25抑制H3 K4 me 3在转录起始位点的细胞去甲基化和MM 1 S多发性骨髓瘤细胞的增殖。
Methylation of lysine residues on histone tail is a dynamic epigenetic modification that plays a key role in chromatin structure and gene regulation. Members of the KDM5 (also known as JARID1) sub-family are 2-oxoglutarate (2-OG) and Fe2+-dependent oxygenases acting as histone 3 lysine 4 trimethyl (H3K4me3) demethylases, regulating proliferation, stem cell self-renewal, and differentiation. Here we present the characterization of KDOAM-25, an inhibitor of KDM5 enzymes. KDOAM-25 shows biochemical half maximal inhibitory concentration values of <100 nM for KDM5A-D in vitro, high selectivity toward other 2-OG oxygenases sub-families, and no off-target activity on a panel of 55 receptors and enzymes. In human cell assay systems, KDOAM-25 has a half maximal effective concentration of ∼50 μM and good selectivity toward other demethylases. KDM5B is overexpressed in multiple myeloma and negatively correlated with the overall survival. Multiple myeloma MM1S cells treated with KDOAM-25 show increased global H3K4 methylation at transcriptional start sites and impaired proliferation. KDOAM-25 is a selective inhibitor of KDM5A-D, the H3K4me3 lysine demethylases KDOAM-25 inhibits the demethylation of H3K4me3 in an immunofluorescence assay Increased KDM5B expression correlates with shorter survival in multiple myeloma KDOAM-25-treated cells show an increase in H3K4me3 at transcription start sites Tumber et al. report the discovery and characterization of KDOAM-25, a potent and selective inhibitor of the KDM5 H3K4me3 lysine demethylases. KDOAM-25 inhibits the cellular demethylation of H3K4me3 at transcription start sites and the proliferation of MM1S multiple myeloma cells.