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小分子诱导的液-液相分离抑制了β-catenin的致癌性

Jin Yan^1,2,3, Heyuan Liu^2,3, Wenguang Yang¹

¹Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, P. R. China.

Nature communications

|July 2, 2025

概括

研究人员开发了一种新的策略,通过诱导它们的相分离成为生物分子凝聚物来向致病蛋白. 一个小分子,RQ,有效地在肝癌细胞中隔离致癌β-catenin,从而导致瘤抑制.

科学领域:

生物化学生物化学
分子生物学分子生物学
癌症研究癌症研究

背景情况:

生物分子凝聚物是没有膜的细胞区,可以隔离蛋白质.
针对缺乏酶活性的疾病驱动蛋白质是传统药物开发的挑战.
目前的凝聚物调节策略无法达到许多这样的蛋白质.

研究的目的:

开发一种替代策略来向以前无法向的蛋白质.
在目标蛋白质中通过不稳定诱导液体-液体相分离 (LLPS).
为由β-catenin驱动的肝癌创造一种新的治疗方法.

主要方法:

开发了一个小分子RQ来破坏目标蛋白质的稳定并诱导LLPS.
利用纳米粒子形式的RQ (与蛋白结合的阿布罗) 进行有针对性的输送.
研究了RQ对beta-catenin在肝癌细胞中的局部化和活性的影响.
在临床前模型中评估了瘤生长抑制和免疫逃避.

主要成果:

RQ成功诱导了β-catenin的细胞质凝聚物,防止核进入.
结合白的阿布罗金选择性地向并杀死β-catenin驱动的肝癌细胞.
这种方法证明了抑制瘤生长和克服免疫逃避.
这种方法为向以前被认为是无毒的蛋白质提供了一个新的范式.

结论:

诱导蛋白质相分离是一种可行的策略,用于向不耐药蛋白质.
对于β-catenin驱动的肝癌,RQ代表了一个有前途的治疗剂.
这种方法有可能在癌症治疗中克服耐药性和免疫逃避.

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