小分子稳定KSR非活性状态对抗瘤性Ras信号
Neil S Dhawan1,2, Alex P Scopton1,2, Arvin C Dar1,2
1Department of Oncological Sciences, The Tisch Cancer Institute, The Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
Nature
|August 25, 2016
概括
研究人员开发了针对Ras的激酶抑制剂 (KSR) 的新化合物,以抑制Ras-mitogen激活蛋白激酶 (MAPK) 途径. 这种方法稳定了不活跃的KSR状态,提供了一种克服Ras驱动癌症的新策略.
科学领域:
- 癌症学
- 分子生物学
- 药物发现
背景情况:
- 在癌症中,Ras-mitogen激活蛋白激酶 (MAPK) 途径失调是常见的,并导致治疗耐药性.
- 在K-Ras的突变往往稳定活跃的RAF信号复合体,维持路径活动.
- 激酶抑制剂的Ras (KSR) 作为一个MAPK支架,由RAF二元化调节.
研究的目的:
- 开发针对KSR功能的小分子抗剂.
- 探索KSR作为克服Ras驱动癌症和针对性治疗的耐药性的治疗点.
- 研究KSR在调节MAPK信号传递中的作用及其药物开发潜力.
主要方法:
- 开发了基于突变选择性抑制瘤性Ras信号的KSR向化合物.
- 使用APS-2-79作为模拟化合物来调节KSR依赖的MAPK信号.
- 评估了APS-2-79对RAF异体化,MEK酸化和KSR激活的影响.
- 在Ras突变细胞系中评估APS- 2-79与MEK抑制剂的疗效.
主要成果:
- 通过新开发的化合物稳定了新的非活性KSR状态.
- 证明APS-2-79对抗RAF异体化和MEK激活.
- 通过阻断负反,显示APS- 2-79增强了Ras突变细胞中的MEK抑制剂功效.
- 证实了KSR形状切换作为瘤性Ras信号的可用调节器.
结论:
- 通过稳定其非活性状态来准KSR是Ras驱动癌症的可行治疗策略.
- Ras-MAPK通路的共同向支架 (KSR) 和酶 (RAF/MEK) 组件可以克服耐药性.
- 开发像APS-2-79这样的KSR抗体有望提高当前MAPK抑制剂的疗效.
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