...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>The FEBS journal >Identification of a novel BCL2-specific inhibitor that binds predominantly to the BH1 domain
【24h】

Identification of a novel BCL2-specific inhibitor that binds predominantly to the BH1 domain

机译：主要与BH1域结合的新型BCL2特异性抑制剂的鉴定

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

The antiapoptotic protein BCL2 is overexpressed in several cancers and contributes to prolonged cell survival and chemoresistance, lending itself as an excellent target for cancer therapy. Here, we report the design, synthesis, and characterization of Disarib, a novel BCL2 inhibitor. Disarib showed selective cytotoxicity in BCL2 high cancer cell lines, and CLL patient primary cells, as compared to BCL2 low cell lines. BCL2 knockdown in cells rendered remarkable resistance to Disarib, while sensitivity was regained upon its ectopic expression, establishing target specificity. In silico, biochemical and biophysical studies demonstrated strong affinity of Disarib to BCL2, but not to other antiapoptotic BCL2 family members viz., BCL-xL, BCL2A1 etc. Interestingly, biophysical studies showed that BH1 domain deletion mutant demonstrated similar to 67-fold reduction in BCL2-Disarib interaction, while it was only similar to 20-fold in the case of BH3 deletion mutant, suggesting predominant involvement of the BH1 domain for Disarib binding. Thus, we report identification of a novel BCL2 inhibitor with a unique mechanism of BCL2 inhibition, as opposed to the well-studied BH3 domain targeting.
机译：抗凋亡蛋白BCL2在几种癌症中过表达，并有助于延长细胞存活率和化学抗性，使其成为癌症治疗的理想靶标。在这里，我们报告新型BCL2抑制剂Disarib的设计，合成和表征。与BCL2低细胞株相比，Disarib在BCL2高癌细胞株和CLL患者原代细胞中显示出选择性的细胞毒性。细胞中的BCL2敲低使Disarib产生了显着的抗性，而异位表达又恢复了敏感性，从而建立了靶标特异性。在计算机上，生物化学和生物物理研究表明Disarib与BCL2有很强的亲和力，但与其他抗凋亡BCL2家族成员（如BCL-xL，BCL2A1等）没有亲和力。有趣的是，生物物理研究表明BH1结构域缺失突变体显示出约67倍的减少在BCL2-Disarib相互作用中，它仅类似于BH3缺失突变体的20倍，表明BH1域主要参与Disarib结合。因此，我们报道了一种具有独特的BCL2抑制机制的新型BCL2抑制剂的鉴定，这与经过充分研究的BH3域靶向相反。

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