在KRAS中对加密和功能口袋的结合剂的识别和表征
Kim S Beyer1, Jessica Klein1, Stéphanie Katz1
1Novartis Biomedical Research, Basel, Switzerland.
Nature communications
|December 2, 2025
概括
研究人员在RAS蛋白中发现了一个新的可用药物的口袋,RAS蛋白是癌细胞增殖的关键驱动因素. 这一发现为克服耐药性和开发新的癌症疗法提供了一种新的策略,通过针对活跃和不活跃的RAS状态来开发新的癌症疗法.
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:
- RAS蛋白对细胞增殖至关重要,它们的激活突变在癌症中很常见.
- 现有的针对RAS的疗法面临抗药性,需要确定新的可用药物的部位.
- 从历史上看,RAS蛋白质的小尺寸和球状性质使它们成为具有挑战性的药物标.
研究的目的:
- 在RAS蛋白中识别新的可向口袋,超出现有的药物结合部位.
- 开发新的治疗策略,以克服对RAS向药物的获得性耐药性.
- 探索针对活跃的 (GTP-bound) 和不活跃的 (GDP-bound) RAS 状态的新方法.
主要方法:
- 使用的宏环 mRNA 和纳米体酵母显示选平台.
- 使用新型KM12和KM12-AM纳米体进行了体外和细胞实验.
- 进行了突变发生的实验,以对发现的结合口袋进行直角验证.
主要成果:
- 在RAS蛋白中发现了一种新的,可向的带诱导的口袋.
- 确定了KM12和KM12-AM纳米体,通过通过cRAF CRD域取代cRAF来抑制RAS.
- 证明发现的口袋允许同时针对GTP和GDP的RAS状态.
- 证实,所识别的方法不会影响Swil口袋,允许组合疗法.
结论:
- 在RAS蛋白中发现了一种新的可用药物的口袋,为癌症治疗提供了一个有前途的途径.
- 发现的纳米体为RAS抑制提供了一种新的机制,有可能克服现有的抗性.
- 这种方法可以同时针对不同的RAS状态和与现有药物结合的策略.
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