发现了五个SOS2碎片与SOS2X射线共晶学确定的绑定模式相撞
Christopher R Smith1, Dan Chen2, James G Christensen1
1Mirati Therapeutics, San Diego, California 92130, United States.
Journal of medicinal chemistry
|December 29, 2023
概括
研究人员使用基于片段的查确定了新的SOS2:KRAS相互作用. 这项工作为开发针对SOS2的新抑制剂铺平了道路,SOS2是一种涉及MAPK反弹的蛋白质,具有治疗潜力.
科学领域:
- 分子生物学分子生物学
- 药物发现 药物发现 药物发现
- 结构生物学 结构生物学
背景情况:
- 七无之子 (SOS) 蛋白,SOS1和SOS2,是关氨酸核酸交换因子,对RAS信号通路至关重要.
- RAS-MAPK通路失调与各种癌症有关,使得RAS通路组件如SOS蛋白成为有吸引力的治疗点.
- 虽然SOS1:KRAS相互作用是抑制剂的目标,但SOS2:KRAS相互作用仍未得到充分探索,尽管SOS2在MAPK反弹中的作用.
研究的目的:
- 确定针对SOS2:KRAS蛋白与蛋白相互作用 (PPI) 的新型抑制剂.
- 用结构生物学技术来描述小分子与SOS2的结合.
- 探索SOS2作为RAS通路激活驱动的癌症的潜在治疗点.
主要方法:
- 基于碎片的药物发现 (FBDD) 方法.
- 不同片段库的高通量选.
- 用X射线晶体学来确定与SOS2结合的碎片碰撞的共同晶体结构.
- 生物化学试验证实了SOS2活动的抑制.
主要成果:
- 识别了与SOS2结合的五个不同的碎片匹配结果.
- 对这些碎片-SOS2复合体的X射线共晶结构的确定.
- 这些结构为设计强大的SOS2:KRAS PPI抑制剂提供了基础.
结论:
- 基于碎片的查是发现SOS2抑制剂的可行策略.
- 已识别的碎片代表了开发针对SOS2的新疗法的起点.
- 准SOS2:KRAS相互作用可能为对SOS1抑制剂有抗性的癌症提供新的治疗途径.
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