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iTAG是一种优化IMiD诱导的降解剂,用于人类和小鼠细胞中向蛋白质降解

Habib Bouguenina¹, Stephanos Nicolaou¹, Yann-Vaï Le Bihan¹

¹Centre for Cancer Drug Discovery, the Institute of Cancer Research, 15 Cotswold Road, Sutton, London SM2 5NG, UK.

|June 26, 2023

概括

研究人员开发了iTAG,这是一个新的合成标签,改进了PROTAC和现有的IMiD/CELMoD系统. 这种多功能工具有效地降解了人类和小鼠蛋白质组中的目标蛋白质,而没有PROTAC的"子效应".

科学领域:

分子生物学分子生物学
药物发现药物发现药物发现
蛋白质组学是指蛋白质组学.

背景情况:

像PROTACs这样的现有的基于降解的系统有局限性,包括"效应".
IMiDs/CELMoDs提供了针对蛋白质降解的机制,但需要改进以获得更广泛的应用.

研究的目的:

开发一种新的合成标签,iTAG,可以克服当前蛋白质降解系统的局限性.
评估iTAG在诱导各种细胞类型和亚细胞局部的蛋白降解方面的有效性.
评估iTAG在人类和小鼠系统中的功能.

主要方法:

系统的结构和序列分析原生和仿制的含降解子域 (DCDs).
评估DCDs诱导蛋白质降解的能力.
鉴定和表征最优的模拟物iTAG (DCD23 60aa).

主要成果:

该iTAG系统,特别是iTAG ((DCD23 60aa),在各种细胞类型和亚细胞区间强有力的诱导目标降解.
iTAG有效地降低了目标,而不表现出PROTAC系统的"子效应"特征.
iTAG证明了与小鼠大脑蛋白 (CRBN) 的功能性,并使得小鼠新基质的探索成为可能.

结论:

iTAG代表了一种针对蛋白质降解的多功能和改进的工具.
该系统克服了 PROTAC 和以前基于 IMiD / CELMoD 的标签的关键限制.
在人类和小鼠模型中,iTAG促进了全蛋白质组的目标降解.

关键词:

生物化学生物化学生物科学生物科学细胞生物学细胞生物学在瘤学瘤学.

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