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开发基于miRNA的PROTACs,针对Lin28进行乳腺癌治疗

Jianfei Xu¹, Xiaoran Zhao¹, Xingxing Liang¹

¹State Key Laboratory of Natural and Biomimetic Drugs, Chemical Biology Center and School of Pharmaceutical Sciences, Peking University, Xueyuan Rd, Beijing 100191, China.

Science advances

|September 18, 2024

概括

研究人员开发了基于miRNA的新型PROTACs来降解Lin28A,这是一种驱动癌症干细胞生成的蛋白质. 这种方法恢复瘤抑制器miRNA let-7,抑制癌症生长并增加化疗敏感性,提供了一个有前途的新型癌症疗法.

科学领域:

在瘤学瘤学.
分子生物学分子生物学
生物化学生物化学

背景情况:

林28是一种受保护的蛋白质,涉及癌症干细胞生成和患者预后不佳.
林28结合并抑制了瘤抑制器微RNA (miRNA) let-7.的成熟.
降低let-7水平促进癌症的进展,包括扩散,入侵,转移和耐药性.

研究的目的:

设计和评估基于miRNA的蛋白质分解向嵌合体 (PROTACs),向Lin28A进行降解.
在临床前癌症模型中研究Lin28A通过PROTACs降解的治疗潜力.

主要方法:

一系列Lin28A-miRNA-PROTACs的开发,旨在诱导Lin28A的依赖于全方位蛋白酶的降解.
评估PROTAC在恢复成熟let-7miRNA水平方面的疗效.
评估Lin28A降解对癌细胞增殖,迁移和化疗敏感性的影响.
在小鼠外宫瘤模型中对Lin28A-miRNA-PROTACs进行体内测试,包括与他莫西芬的联合治疗.

主要成果:

开发出来的Lin28A-miRNA-PROTACs通过一种全素-蛋白酶体通路有效降解Lin28A.
林28A的降解导致成熟的let-7miRNAs的显著上调.
恢复的let-7水平抑制了癌细胞的增殖和迁移,并增强了化疗的敏感性.
在体内,Lin28A-miRNA-PROTACs表现出显著的瘤生长抑制,与他莫西芬结合时显著回归.

结论:

基于miRNA的PROTACs是针对Lin28A.的有针对性的降解的有效策略.
这种方法恢复了瘤抑制剂miRNA let-7的活性,从而抑制了癌症的进展.
Lin28A-miRNA-PROTACs在癌症治疗中显示出显著的治疗前景,特别是在组合疗法中.

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