Plant growth regulator daminozide is a selective inhibitor of human KDM2/7 histone demethylases.
Plant growth regulator daminozide is a selective inhibitor of human KDM2/7 histone demethylases.
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DOI：
10.1021/jm300677j
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发表时间：
2012-07-26
影响因子：
7.3
通讯作者：
Kawamura A
中科院分区：
文献类型：
--
作者：
Rose NR;Woon EC;Tumber A;Walport LJ;Chowdhury R;Li XS;King ON;Lejeune C;Ng SS;Krojer T;Chan MC;Rydzik AM;Hopkinson RJ;Che KH;Daniel M;Strain-Damerell C;Gileadi C;Kochan G;Leung IK;Dunford J;Yeoh KK;Ratcliffe PJ;Burgess-Brown N;von Delft F;Muller S;Marsden B;Brennan PE;McDonough MA;Oppermann U;Klose RJ;Schofield CJ;Kawamura A
JmjC加氧酶催化组蛋白中Nε-甲基赖氨酸残基的N-去甲基化，并且是当前的治疗靶点。使用JmjC脱甲基酶和相关加氧酶的统一测定平台筛选一组2-酮戊二酸类似物。结果导致发现，植物生长调节剂丁酰肼（N-（二甲基氨基）琥珀酰胺酸，160 Da）选择性地抑制KDM 2/7 JmjC亚家族。动力学和晶体学研究表明，daminozide螯合活性位点金属通过其酰肼羰基和二甲氨基。
The JmjC oxygenases catalyse the N-demethylation of Nε-methyl lysine residues in histones and are current therapeutic targets. A set of 2-oxoglutarate analogues were screened using a unified assay platform for JmjC demethylases and related oxygenases. Results led to the finding that daminozide (N-(dimethylamino)succinamic acid, 160 Da), a plant growth regulator, selectively inhibits the KDM2/7 JmjC subfamily. Kinetic and crystallographic studies reveal daminozide chelates the active site metal via its hydrazide carbonyl and dimethylamino groups.