细胞内膜网膜应激传感器 IRE1 的化学诱导降解是由一个 VHL 招募的仿真体所造成的
Jin Du1, Elisia Villemure2, Matthew Johnson3
1Department of Research Oncology, Genentech, Inc., South San Francisco, CA, USA.
Nature communications
|December 11, 2025
概括
一种针对蛋白质溶解的新型嵌合体 (G6374) 有效地降解了内质网膜 (ER) 蛋白 IRE1,这是癌症生长的关键驱动因素. 这种有针对性的降解提供了一种新的策略来对抗依赖IRE1的癌症.
科学领域:
- 分子生物学分子生物学
- 癌症研究 癌症研究
- 药物发现 药物发现 药物发现
背景情况:
- 细胞内膜网膜 (ER) 蛋白 IRE1 对于减轻 ER 压力至关重要,但癌细胞经常利用它来生长.
- 虽然IRE1-RNase抑制剂正在临床试验中,但癌症中显著的非酶性IRE1依赖性需要替代治疗策略.
- 为了有效治疗癌症,完全破坏 IRE1 功能至关重要.
研究的目的:
- 开发一种新的治疗策略,以完全破坏癌细胞中的IRE1功能.
- 研究向蛋白质溶解的嵌合体 (PROTACs) 降解IRE1.1的潜力.
- 描述一款新设计的针对 IRE1 的 PROTAC 的机制和功效.
主要方法:
- 一个向蛋白解的嵌合体 (G6374) 的设计和合成,该嵌合体将 IRE1-激酶配体与 VHL E3 配体结合起来.
- 评估G6374诱导的IRE1通过K48链接的无化和蛋白质酶体通路的降解.
- 使用冷电子显微镜和突变发生的IRE1:VHL复合物的结构阐明.
- 评估G6374在阻断IRE1依赖癌细胞生长方面的疗效.
主要成果:
- G6374成功地诱导了IRE1和VHL之间的稳定,合作相互作用,导致IRE1.1的蛋白质体降解.
- 冷-EM和突变发生学揭示了2:2 IRE1:VHL三元复合结构,为结合相互作用提供了洞察力.
- 无论其具体的依赖机制如何,G6374有效地抑制了依赖IRE1的癌细胞的生长.
- 该化合物表现出选择性,节省了IRE1独立的细胞.
结论:
- 针对蛋白质分解的嵌合体代表了在癌症中完全破坏IRE1的可行策略.
- G6374提供了基于VHL的ER-跨膜蛋白质降解的概念证明,如IRE1.1.
- 这种方法为依赖IRE1信号传递的癌症治疗提供了一个有希望的新途径.
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