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针对蛋白质溶解的嵌合体具有减少的非目标

Tuan M Nguyen^1,2,3, Vedagopuram Sreekanth^1,2,3, Arghya Deb^1,2

¹Chemical Biology and Therapeutics Science, Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Nature chemistry

|December 18, 2023

概括

使用波马利多米德的蛋白质溶解向金像体 (PROTACs) 可以降解意外的指蛋白. 修改波马利多米德的方法

科学领域:

生物化学生化学
分子生物学分子生物学
药物发现药物发现药物发现

背景情况:

向蛋白质分解的嵌合体 (PROTACs) 利用E3链酶进行向蛋白质降解.
利多米德是PROTAC中常见的E3酶招募剂,它表现出指 (ZF) 蛋白的非目标降解.
这种非目标效应限制了基于波马利多米德的PROTACs的治疗潜力.

研究的目的:

为了调查和减轻由利多米德基PROTACs诱导的非目标指蛋白降解.
建立PROTAC设计原则,尽量减少意外的蛋白质降解.
开发更高效率和特异性的改进的PROTAC.

主要方法:

开发一个高吞吐量平台,用于询问非目标降解.
合成和选的图书馆的pomalidomide类似物与修改在phthalimide环.
评估对ZF蛋白质降解的结,硬质和疏水效应.
使用目标参与测试和蛋白质组学进行验证.
设计和测试对形淋巴瘤激酶 (ALK) 在基蛋白向的PROTACs.

主要成果:

现有的基于波马利多米德的PROTAC被证实会降解多个ZF蛋白.
在甲胺环的C5位置的修改有效地减少了非目标ZF蛋白降解.
结构-活动关系研究阐明了影响非目标效应的关键因素.
新型向ALK的PROTACs表现出强度增加,并且显著减少了目标外降解.

结论:

战略性修改波马利多米德类似物可以最大限度地减少非目标ZF蛋白降解.
这些发现为开发更安全,更有效的PROTAC提供了关键的设计规则.
开发的PROTACs代表了针对性癌症治疗的有希望的进步,以ALK抑制为例.

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