• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Nature >Small molecule stabilization of the KSR inactive state antagonizes oncogenic Ras signalling
【24h】

Small molecule stabilization of the KSR inactive state antagonizes oncogenic Ras signalling

机译：KSR非活性状态的小分子稳定化拮抗致癌的Ras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

Deregulation of the Ras-mitogen activated protein kinase (MAPK) pathway is an early event in many different cancers and a key driver of resistance to targeted therapies'. Sustained signalling through this pathway is caused most often by mutations in K-Ras, which biochemically favours the stabilization of active RAF signalling complexes'. Kinase suppressor of Ras (KSR) is a MAPK scaffold(3-5) that is subject to allosteric regulation through dimerization with RAF(6,7). Direct targeting of KSR could have important therapeutic implications for cancer; however, testing this hypothesis has been difficult owing to a lack of small-molecule antagonists of KSR function. Guided by KSR mutations that selectively suppress oncogenic, but not wild-type, Ras signalling, we developed a class of compounds that stabilize a previously unrecognized inactive state of KSR. These compounds, exemplified by APS-2-79, modulate KSR-dependent MAPK signalling by antagonizing RAF heterodimerization as well as the conformational changes required for phosphorylation and activation of KSR-bound MEK (mitogen-activated protein kinase kinase). Furthermore, APS-2-79 increased the potency of several MEK inhibitors specifically within Ras mutant cell lines by antagonizing release of negative feedback signalling, demonstrating the potential of targeting KSR to improve the efficacy of current MAPK inhibitors. These results reveal conformational switching in KSR as a druggable regulator of oncogenic Ras, and further suggest co-targeting of enzymatic and scaffolding activities within Ras-MAPK signalling complexes as a therapeutic strategy for overcoming Ras-driven cancers.
机译：Ras丝裂原活化蛋白激酶（MAPK）通路的失调是许多不同癌症中的早期事件，并且是对靶向疗法耐药的关键驱动力。通过该途径持续的信号转导通常是由K-Ras突变引起的，这在生化上有利于稳定活性RAF信号转导复合物。 Ras激酶抑制剂（KSR）是一种MAPK支架（3-5），可通过与RAF（6,7）进行二聚化来进行变构调节。直接靶向KSR可能对癌症具有重要的治疗意义；但是，由于缺乏KSR功能的小分子拮抗剂，因此很难验证这一假设。在选择性抑制致癌性而非野生型Ras信号的KSR突变的指导下，我们开发了稳定一类先前无法识别的KSR失活状态的化合物。这些化合物以APS-2-79为例，通过拮抗RAF异源二聚化以及磷酸化和激活KSR结合的MEK（促分裂原活化的蛋白激酶激酶）所需的构象变化，来调节KSR依赖性MAPK信号传导。此外，APS-2-79通过拮抗负反馈信号的释放，提高了几种MEK抑制剂在Ras突变细胞系中的效力，证明了靶向KSR改善当前MAPK抑制剂功效的潜力。这些结果揭示了KSR中的构象转换是致癌性Ras的可药物调节剂，并且进一步暗示了Ras-MAPK信号复合物中酶和支架活性的共同靶向是克服Ras驱动的癌症的治疗策略。

著录项

  • 来源
    《Nature》 |2016年第7618期|112-116|共5页
  • 作者

    Dhawan Neil S.; Scopton Alex P.; Dar Arvin C.;

  • 作者单位

    Icahn Sch Med Mt Sinai, Tisch Canc Inst, Dept Oncol Sci, New York, NY 10029 USA|Icahn Sch Med Mt Sinai, Tisch Canc Inst, Dept Struct & Chem Biol, New York, NY 10029 USA;

    Icahn Sch Med Mt Sinai, Tisch Canc Inst, Dept Oncol Sci, New York, NY 10029 USA|Icahn Sch Med Mt Sinai, Tisch Canc Inst, Dept Struct & Chem Biol, New York, NY 10029 USA;

    Icahn Sch Med Mt Sinai, Tisch Canc Inst, Dept Oncol Sci, New York, NY 10029 USA|Icahn Sch Med Mt Sinai, Tisch Canc Inst, Dept Struct & Chem Biol, New York, NY 10029 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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