通过诱导近距离的有针对性的转录抑制
bioRxiv : the preprint server for biology
|November 24, 2025
概括
一种称为通过表观遗传重编程 (TRACER) 积极控制的转录调节的新疗法通过招募表观遗传抑制剂来沉默不可抗药的癌症驱动转录因子. 这种表观遗传重编程策略为难以治疗的癌症提供了一种新的治疗方法.
科学领域:
- 在瘤学瘤学.
- 表观遗传学 在表观遗传学中,表观遗传学是指表观遗传学.
- 药物发现 药物发现 药物发现
背景情况:
- 许多癌症驱动蛋白质,特别是转录因子,由于缺乏口袋和依赖蛋白质-DNA / 蛋白质-蛋白质相互作用,是不可抗药的.
- 转录因子是具有挑战性的目标,因为它们的转换速度很快,对抑制的抵抗力,以及逃避蛋白质降解策略.
研究的目的:
- 引入一种新的诱导近距离治疗模式,TRACER,用于有针对性的转录沉默.
- 在癌症模型中证明TRACER在抑制雌激素受体 (ER) 和雄激素受体 (AR) 的有效性.
主要方法:
- 开发小分子TRACER来绑定MBD2和NuRD复合体到转录因子配体.
- 在乳腺癌细胞中应用ER-TRACER,在前列腺癌细胞中应用AR-TRACER.
- 对TRACER进行模块化重编程,以招募像PRC2.2这样的替代抑制剂.
主要成果:
- 在乳腺癌中,ER-TRACER强烈抑制了ER转录活性,并降低了依赖MBD2和HDACs的目标基因的下调.
- 在前列腺癌细胞中,AR-TRACER实现了全长AR和AR-V7活性>90%的抑制.
- 追踪器证明了模块性,使得不同的核心压缩器复合体可以用于向的基因抑制.
结论:
- 通过表观遗传学重编程,TRACERs代表了一种可通用的方法,通过表观遗传学重编程来药理上沉默无药的转录因子.
- 这种方法提供了一个有前途的新策略来治疗对当前疗法的耐药性癌症.
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