共价抑制剂的设计赋予了对KRAS G12C的GDP和GTP结合形式的活性
Matthew L Condakes1, Zhuo Zhang2, Derek B Danahy2
1Bristol Myers Squibb, 250 Water St., Cambridge, MA, USA. matthew@condakes.com.
Nature communications
|January 31, 2026
概括
研究人员开发了双重的KRAS G12C抑制剂,针对非活性和活性状态. 这些新型抑制剂显示出有希望的结果,但在临床前模型中,它们对选择性抑制剂没有任何机械优势.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 药物发现 药物发现 药物发现
背景情况:
- KRAS G12C突变驱动癌症,针对其不活跃状态的抑制剂已获得临床批准.
- 针对不活跃和活跃的KRAS G12C状态仍然是不发达的.
- 交换机II (SWII) 结合抑制剂提供了一个潜在的治疗策略.
研究的目的:
- 发现和描述新型KRAS G12C双抑制剂.
- 研究双重抑制剂的作用机制.
- 为了比较双重抑制剂与非活性状态选择性抑制剂的疗效.
主要方法:
- 新型共价抑制剂的化学合成.
- 共同晶体结构的确定.
- 细胞测试测量MAPK信号传递.
- 在临床前模型中的体内疗效研究.
主要成果:
- 发现双重KRAS G12C抑制剂结合SWII部位.
- 结构数据揭示了水媒介网络的破坏和全重塑.
- 双重抑制剂实现了快速的目标参与和MAPK通路抑制.
- 在细胞和体内模型中观察到双重和非活性状态选择性抑制剂的类似疗效.
- 这两种抑制剂类别在增长因子的存在下表现出可比的疗效.
结论:
- 首次详细描述了针对活动和非活动KRAS G12C状态的目标.
- 双重抑制剂提供快速的目标失活,但与选择性抑制剂相比没有机械优势.
- 需要长时间的制目标的情况不需要双重抑制剂.
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