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Updated: Apr 8, 2026

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发现了一种强效和选择性的蛋白质氨酸甲基转移酶5 (PRMT5) PROTAC降解剂

Yue Zhong^1,2,3, Huensuk Kim^1,2,3, Chao Qian^1,2,3

¹Mount Sinai Center for Therapeutics Discovery, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.

Journal of medicinal chemistry

|April 15, 2025

概括

研究人员开发了一种强大的PRMT5降解剂MS115,以向癌症. 这种新化合物有效降解PRMT5/MEP50复合体,显示出作为癌症治疗和化学生物学工具的希望.

科学领域:

生物化学生物化学
分子生物学分子生物学
在瘤学瘤学.

背景情况:

蛋白质氨酸甲基转移酶5 (PRMT5) 对生物过程至关重要,其过度表达与癌症预后不佳有关.
·希佩尔-林道 (VHL) E3结合酶复合体是蛋白质降解疗法的目标.
之前的开发成果是MS4322,这是第一个采用VHL的PRMT5降解器.

研究的目的:

通过结构-活性关系 (SAR) 研究,优化PRMT5降解剂.
确定一种具有增强功效和选择性的最佳类型PRMT5降解剂.
在癌症模型中评估新型PRMT5降解剂的治疗潜力.

主要方法:

对VHL和PRMT5连接体和链接体进行了SAR研究.
合成和描述了新型PRMT5降解剂,包括化合物10 (MS115).
评估了癌细胞中PRMT5和MEP50的降解,检查了度,时间和无素-蛋白酶体系统的依赖性.

主要成果:

确定MS115 (化合物10) 是一类中最好的PRMT5降解剂,其功效明显提高了MS4322.
证明了PRMT5/MEP50复合物的强大和选择性降解,以时间,度和无素-蛋白酶体系统依赖的方式.
观察到MS115在乳腺癌和前列腺癌细胞中的抗增殖作用优于MS4322.

结论:

发现了MS115,它是PRMT5/MEP50复合物的高强度和选择性降解剂.
MS115代表了一种有价值的化学生物学工具,用于研究PRMT5功能.
MS115显示出作为癌症治疗新型治疗剂的巨大潜力.

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