一个模块化化学平台,用于开发一个基于Cereblon E3联酶的部分 PROTAC 库
Chelsi M Almodóvar-Rivera1, Zhen Zhang1, Jingyao Li1
1Lachman Institute for Pharmaceutical Development, School of Pharmacy, University of Wisconsin-Madison, 777 Highland Avenue, Madison, WI, 53705, USA.
Chembiochem : a European journal of chemical biology
|July 7, 2023
概括
研究人员开发了一种新方法,使用修饰的莱纳利多米德制造蛋白质溶解向金马 (PROTACs). 该平台允许系统地调查PROTAC开发中针对蛋白质降解的链接效应.
科学领域:
- 药用化学 医学化学
- 化学生物学 化学生物学
- 药物发现 药物发现 药物发现
背景情况:
- 针对蛋白质溶解的定向嵌合体 (PROTACs) 为向蛋白质降解提供了一种新的治疗策略.
- 像莱纳利多米德一样,Cereblon (CRBN) E3酶配体是PROTAC开发中的关键组成部分.
- 之前的研究表明,莱纳利多米德对PROTACs具有C4-替代耐受性.
研究的目的:
- 建立一个模块化化学平台,用于合成各种来自lenalidomide的CRBN E3酶连接物.
- 为了能够系统地调查PROTAC开发中的链接效应.
- 扩大创建针对各种蛋白质的 PROTAC 的工具包.
主要方法:
- 利用苏苏基交叉合反应,以有效地将替代的基组连接到莱纳利多米德的C4位置.
- 合成了12种新的lenalidomide衍生物,具有不同的链接器功能.
- 探索了正,元和替代的基修饰.
主要成果:
- 成功开发了一个多功能平台,用于创建修改的基于lenalidomide的CRBN配体.
- 证明了连接各种替代剂和链接剂的可行性.
- 为 PROTAC 开发生成了一个 12 个新连接体的库.
结论:
- 建立的平台有助于系统地研究PROTAC设计中的链接效应.
- 这种方法促进了针对蛋白质降解治疗的新型PROTACs的开发.
- 该方法为创建针对更广泛的蛋白质标的PROTACs提供了基础.
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