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Updated: Jul 2, 2025

Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs

Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs

Published on: May 15, 2019

对有效的CBP/p300异位生物功能降解剂活性进行基基因连接体-链接体结合部位的探索

Praveen Kumar Tiwari¹, Sai Reddy Doda¹, Raghu Vannam¹

¹Krantz Family Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA, USA; Harvard Medical School, Boston, MA, USA.

Bioorganic & medicinal chemistry letters

|February 26, 2024

概括

这项研究探讨了原体连接体上的链接器附着部位如何影响蛋白质溶解向嵌合体 (PROTAC) 的有效性. 优化链接器的放置是开发针对CBP/p300蛋白质的有力PROTACs的关键.

科学领域:

化学生物学化学生物学
表观遗传学在表观遗传学中,表观遗传学是指表观遗传学.
药物发现药物发现药物发现

背景情况:

化向化体 (PROTACs) 是双功能分子,它们招募E3酶以向蛋白质进行降解.
含有基因的蛋白质,如CBP/p300,是参与基因调节的表观遗传读者,是经过验证的治疗标.
设计PROTACs需要仔细考虑连接器的长度和粘附点,无论是在目标结合联结体和E3联结酶联结体.

研究的目的:

调查不同链接器附着点 (出口载体) 和长度对CBP/p300 PROTACs降解活性的影响.
分析三元复合物的形成,这对于高效的PROTAC介导降解至关重要.
为CBP/p300降解剂 (dCBPs) 图书馆建立结构-活动关系.

主要方法:

一个多样化的CBP/p300 PROTACs库的合成,具有不同的链接器结合点和长度.
动力活细胞测试测量内源性CBP和p300蛋白质的降解.
基于珠子的近距离测试来量化三元复合形成.

主要成果:

不同的链接器附着部位和长度显著影响了针对CBP和p300的PROTAC降解活性.
优化的链接器策略增强了三元复合体的形成,导致更有效的蛋白质降解.
阐明了结构-活动关系,提供了对原体目标的合理 PROTAC 设计的见解.

结论:

链接器结合部位是PROTAC对CBP/p300原体标的疗效的关键决定因素.
考虑链接器几何和长度的合理设计对于开发强大和选择性的PROTAC至关重要.
这项工作为优化针对表观遗传读者和其他蛋白质家族的PROTAC提供了一个框架.

关键词:

乙转移酶的作用是什么美国中央银行 (CBP) 的CBP.这就是PROTAC.一个三角形复合体.在P300上,P300是P300.

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