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通过使用β-酸电友:支持向蛋白质降解的蛋白质和目标发现

Xinyao Ouyang¹, Xiaomeng Chai¹, Lei Huang¹

¹State Key Laboratory of Bioactive Molecules and Druggability Assessment, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development (MOE), School of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China.

Angewandte Chemie (International ed. in English)

|June 4, 2025

概括

研究人员开发了一种用于向蛋白质降解 (TPD) 的新型β-酸化学探针. 这种新的共价核弹头有效地准以前无法获得的蛋白质,并通过激活新的E3链酶 (如TRIM28.8) 来增强抗癌效应.

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:

生物结合化学可以实现蛋白质组向和E3结合酶识别,用于向蛋白质降解 (TPD).
现有的共价探头在访问蛋白质组的重要部分方面存在局限性.
需要新的化学策略来扩大可药物标的范围.

研究的目的:

开发一种新的氨酸向可逆共价核弹头,用于目标发现.
为了确定针对蛋白质降解的新型结合性位点和E3结合酶.
为了创建强大的单价降解剂,增强抗癌功效.

主要方法:

将电子吸收组纳入 styrene 衍生物中以产生 β-nitrostyrene.
现型查和化学蛋白质组学,以确定标蛋白和可结合部位.
将弹头纳入已知的抑制剂 (例如, (+) -JQ1) 中,并评估蛋白质降解和抗癌作用.

主要成果:

确定β-尼托烯作为一种向氨酸的可逆共价核弹头.
发现了新的可结合的位点 (例如,SND1的C96,PTGES2的C110),并确定TRIM28为TPD的新型E3结合酶.
证明了多个标 (EGFR,PDE5,BTK,LRRK2,BCR-ABL/c-ABL) 的有效降解,没有效应.
与相应的抑制剂相比,实现了显著增强的抗癌作用.

结论:

β-酸是一种多用途的共价弹头,用于发现新目标和开发强大的单价降解剂.
这项研究报告了第一个利用TRIM28进行向蛋白质降解的小分子降解剂.
为开发新型和有效的向蛋白质降解剂提供了合理的设计策略.

关键词:

化学蛋白质组学化学蛋白质组学 E3 连接酶的使用.在 TRIM2828 中,目标发现目标发现.乙-酸铁烯 (β-nitrostyrene) 是一种酸铁烯 (β-nitrostyrene) 的一种化合物.

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