一种选择性的jumonji H3K27脱甲基酶抑制剂调节了促炎性巨细胞反应
Laurens Kruidenier1, Chun-wa Chung, Zhongjun Cheng
1Epinova DPU, Immuno-Inflammation Therapy Area, GlaxoSmithKline R&D, Medicines Research Centre, Stevenage SG1 2NY, UK.
Nature
|July 31, 2012
概括
研究人员开发了第一个选择性小分子抑制剂,用于JMJD3和UTX (KDM6亚系) 基因组脱甲基酶. 这一突破澄清了它们在炎症中的作用,并使得针对相关疾病的向药物开发成为可能.
科学领域:
- 生物化学 生物化学
- 表观遗传学 在表观遗传学中,表观遗传学是指表观遗传学.
- 分子生物学分子生物学
背景情况:
- 朱蒙吉 (JMJ) 基因组脱甲基酶调节基因转录和表观遗传.
- 由于缺乏选择性抑制剂,JMJ脱甲基酶活性在细胞反应中的功能作用尚不清楚.
- 具体而言,KDM6亚家族 (JMJD3和UTX) 脱甲基化了H3K27me3.
研究的目的:
- 使用结构导向方法阐明H3K27me3特异性脱甲基酶亚家族 (KDM6) 的功能作用.
- 开发第一个针对H3K27me3特异性JMJ亚家族的选择性小分子催化位抑制剂.
- 研究JMJD3和UTX在调节炎症反应中的作用.
主要方法:
- 结构导向药物设计和化学蛋白质组学.
- 对人类和小鼠的结合结构的确定JMJD3.3.
- 为KDM6亚家族选择性新型小分子抑制剂的生成和测试.
- 评估抑制剂在降低人类巨细胞中脂多糖糖类诱导的细胞因子产生方面的疗效.
主要成果:
- 通过KDM6脱甲基酶对辅因子,基质和抑制剂的识别进行新的结构洞察.
- 开发第一个选择性小分子抑制剂,针对H3K27me3特异性JMJ脱甲基酶的催化位点.
- 证明该抑制剂以一种新的方式结合.
- 在人类巨细胞中显著减少了促炎性细胞因子的产生,这取决于JMJD3和UTX.
- 澄清H3K27特异性JMJs在炎症反应中的催化功能.
结论:
- 这项研究解决了有关H3K27特异性JMJs在疾病相关炎症反应中的催化作用的模两可.
- 开发的小分子抑制剂为药理干预提供了有价值的工具.
- 这些发现鼓励为更广泛的JMJ家族设计选择性抑制剂,用于治疗应用.
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