植物生长调节剂二甲胺嗪是一种选择性的人 KDM2/7 组蛋白去甲基酶抑制剂。
Plant growth regulator daminozide is a selective inhibitor of human KDM2/7 histone demethylases.
机构信息
Epigenetic Regulation of Chromatin Function Group, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, U.K.
出版信息
J Med Chem. 2012 Jul 26;55(14):6639-43. doi: 10.1021/jm300677j. Epub 2012 Jul 11.
Abstract
The JmjC oxygenases catalyze the N-demethylation of N(ε)-methyl lysine residues in histones and are current therapeutic targets. A set of human 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 that daminozide chelates the active site metal via its hydrazide carbonyl and dimethylamino groups.
摘要
JmjC 氧还酶催化组蛋白中 N(ε)-甲基赖氨酸残基的 N-去甲基化，是目前的治疗靶点。使用统一的 JmjC 脱甲基酶和相关氧还酶测定平台筛选了一组人 2-氧戊二酸类似物。结果发现，一种植物生长调节剂（N-(二甲氨基)琥珀酰胺酸，160Da），选择性抑制 KDM2/7 JmjC 亚家族。动力学和晶体学研究表明，达米诺嗪通过其酰肼羰基和二甲氨基与活性位点金属螯合。
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