氨酸-N-乙胺联体对氨酸有反应,可诱导铁死介导的细胞死亡
Gina Gotthardt1, Janik Weckesser2,3, Georg Tascher1
1Institute of Biochemistry II, Goethe University Frankfurt, Faculty of Medicine, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany.
EMBO reports
|October 16, 2025
概括
针对RNF4治疗AML的共价抑制剂由于与目标蛋白结合而失败. 这些抑制剂中的-N-乙胺组会诱导铁亡,这是一种独立于RNF4的细胞死亡途径,突出显示了毒性问题.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 在瘤学瘤学.
背景情况:
- 协同抑制剂提供了一种针对RNF4等难以解决的蛋白质的策略,这种蛋白质在急性髓性白血病 (AML) 中具有潜在的脆弱性.
- 高RNF4表达与AML患者的生存率差相关,其耗尽增加了对抗白血病药物的敏感性.
研究的目的:
- 开发用于RNF4降解的蛋白质分解向嵌合体 (PROTACs),使用已知的共价联体,CCW16.
- 研究基于CCW16的PROTACs的细胞活动和特异性.
主要方法:
- 合成CCW16衍生的PROTACs,其中包含E3酶配体 (CRBN,VHL).
- 在体外测试对重组RNF4的共价结合.
- 细胞测试以评估RNF4降解,蛋白质结合和细胞活力.
- 对铁灭菌标记物和目标外效应的分析.
主要成果:
- 在实验室中,CCW16及其PROTACs对RNF4进行共价结合,但表现出广泛的外结合细胞蛋白,包括过氧化素.
- 基于CCW16的PROTACs未能降解RNF4,而是诱导血红氧酶-1,一种铁亡标志物.
- 这些化合物通过RNF4独立的ferroptotic通路损害了细胞活力.
- 另一种-N-乙胺连接体EN219也诱导了铁,这表明这种电爱因素会导致毒性.
结论:
- 在CCW16中-N-乙胺部分导致非目标毒性和铁亡,独立于RNF4降解.
- 基于CCW16的RNF4向PROTACs由于这些毒性,不适合用于AML治疗.
- 带有-N-乙胺电的配体可能会导致不必要的非目标铁毒性毒性.
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