使用共价G12C特定抑制剂向KRAS突变癌症
Matthew R Janes1, Jingchuan Zhang1, Lian-Sheng Li1
1Wellspring Biosciences, San Diego, CA, USA.
Cell
|January 27, 2018
概括
一种名为ARS-1620的新药在体内有效向KRAS G12C突变,显示出癌症治疗的前景. 这种共价抑制剂实现了持续的点占用和瘤回归,验证了KRAS G12C作为可用药物的点.
科学领域:
- 癌症学
- 分子生物学
- 药物发现
背景情况:
- KRAS G12C突变是各种癌症的一个关键驱动因素.
- 针对KRAS G12C需要访问Switch II口袋 (S-IIP),该口袋仅在GDP-bound状态下可用.
- 之前的体外研究表明可行性,但体内疗效仍不确定.
研究的目的:
- 设计和确定一种强效和选择性的对KRAS G12C的共价抑制剂.
- 评估已识别的抑制剂的体内位和治疗潜力.
- 使用开发的抑制剂在体内调查瘤性KRAS依赖性.
主要方法:
- 使用基于结构的药物设计来识别ARS-1620.
- 在体内研究评估了点占用率和瘤回归.
- 用单层细胞培养和体内模型来剖析KRAS的依赖性.
主要成果:
- 鉴定出ARS-1620,这是KRAS G12C的有力和选择性的共价抑制剂.
- 在体内,ARS-1620表现出快速且持续的目标占用,导致瘤回归.
- 传统单层培养方法显著低估了体内KRAS的依赖性.
结论:
- 突变KRAS G12C可以在体内进行选择性向.
- ARS-1620是一种具有显著治疗潜力的新一代KRAS G12C特异性抑制剂.
- 在体内模型对于准确评估瘤性KRAS依赖性和药物疗效至关重要.
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