• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Cellular Signalling >A novel small molecule deubiquitinase inhibitor blocks Jak2 signaling through Jak2 ubiquitination
【24h】

A novel small molecule deubiquitinase inhibitor blocks Jak2 signaling through Jak2 ubiquitination

机译：新型小分子去泛素酶抑制剂通过Jak2泛素化阻断Jak2信号传导

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

AG490 is a tyrosine kinase inhibitor with activity against Jak2 and apoptotic activity in specific leukemias. Due to its weak kinase inhibitory activity and poor pharmacology, we conducted a cell-based screen for derivatives with improved Jak2 inhibition and activity in animals. Two hits emerged from an initial small chemical library screen, and more detailed structure-activity relationship studies led to the development of WP1130 with 50-fold greater activity in suppressing Jak2-dependent cytokine signaling than AG490. However, WP1130 did not directly suppress Jak2 kinase activity, but mediated Jak2 ubiquitination resulting in its trafficking through HDAC6 to perinuclear aggresomes without cytokine stimulation or SOCS-1 induction. Jak2 primarily contained K63-linked ubiquitin polymers, and mutation of this lysine blocked Jak2 ubiquitination and mobilization in WP1130-treated cells. Further analysis demonstrated that WP1130, but not AG490, acts as a deubiquitinating enzyme (DUB) inhibitor, possibly through a Michael addition reaction. We conclude that chemical modification of AG490 resulted in development of a DUB inhibitor with activity against a DUB capable of modulating Jak2 ubiquitination, trafficking and signal transduction.
机译：AG490是一种酪氨酸激酶抑制剂，在特定的白血病中具有抗Jak2活性和凋亡活性。由于其弱的激酶抑制活性和不良的药理作用，我们进行了基于细胞的筛选，以筛选出具有改善的Jak2抑制作用和动物活性的衍生物。从最初的小型化学文库筛选中发现了两个结果，并且更详细的结构-活性关系研究导致WP1130的发展，其抑制Jak2依赖性细胞因子信号传导的活性比AG490高50倍。但是，WP1130并没有直接抑制Jak2激酶活性，而是介导了Jak2泛素化，导致其通过HDAC6转运到核周聚集体而没有细胞因子刺激或SOCS-1诱导。 Jak2主要包含K63连接的泛素聚合物，该赖氨酸的突变会阻止WP1130处理的细胞中的Jak2泛素化和动员。进一步的分析表明，可能通过迈克尔加成反应，WP1130（而非AG490）充当去泛素化酶（DUB）抑制剂。我们得出结论，AG490的化学修饰导致了DUB抑制剂的开发，该抑制剂具有针对能够调节Jak2泛素化，运输和信号转导的DUB的活性。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号