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N'‐(1-乙烯) 基化细胞毒性是氨酸特异性脱甲基酶1独立且与Ewing肉 Sarcoma中铁硫集群干扰相关

John W Sherman¹, Galen C Rask¹, Bingcong Xiong²

¹Center for Childhood Cancer Research, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio 43215, United States.

ACS pharmacology & translational science

|November 20, 2025

概括

SP-2509和SP-2577,氨酸特异性去甲基酶1 (LSD1) 抑制剂,显示尤文肉瘤活性. 它们的细胞死亡机制独立于LSD1抑制,与铁代谢中断和电子运输链不稳定有关.

科学领域:

在瘤学瘤学.
生物化学生物化学
分子生物学分子生物学

背景情况:

氨酸特异性去甲基酶1 (LSD1) 抑制剂SP-2509和SP-2577通过准EWSR1::FLI1.1,对尤宁肉瘤有效.
以前的研究表明,SP-2509的疗效可能源于非目标线粒体效应,因为其他LSD1抑制剂缺乏类似的活性.

研究的目的:

为了阐明N'-(1-phenylethylidene) -benzohydrazides,包括SP-2509.9,包括SP-2509.9,的目标之外的机制.
研究LSD1抑制与其他细胞过程在SP-2509抗癌作用中的作用.

主要方法:

细胞热转移测定与质谱学 (CETSA-MS) 结合,以确定蛋白质标.
化学和遗传工具来评估SP-2509的作用机制和细胞死亡途径.

主要成果:

CETSA-MS确定了电子输送链复合物III的组成部分ubiquinol-cytochrome c减少酶 (UQCRFS1),该复合物被SP-2509.9破坏稳定.
SP-2509广泛破坏细胞铁硫 (Fe-S) 蛋白质的稳定,影响铁的新陈代谢.
SP-2509诱导的细胞死亡和EWSR1::FLI1调节逆转是独立于LSD1抑制的,与N'-(2-基基) -基化核和Fe-S蛋白质不稳定有关.

结论:

在尤文肉瘤中,SP-2509的抗癌活性主要通过对铁代谢和Fe-S蛋白稳定性的非目标影响来介导,而不是LSD1抑制.
这些发现揭示了化化合物的新型作用机制,并突出了针对癌症铁代谢的潜在治疗策略.

关键词:

这就是CETSA.尤文肉瘤 (Ewing Sarcoma) 是一种癌症.铁的代谢铁的代谢铁-硫集群是一种铁-硫集群.线粒体中的线粒体.

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