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Updated: May 6, 2026

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发现了第一级G9a/GLP PROTAC降解器

Julia Velez¹, Yulin Han¹, Hyerin Yim¹

¹Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Science, Oncological Science, and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.

Journal of medicinal chemistry

|April 11, 2024

概括

首个针对G9a/GLP蛋白质分解的化体 (PROTAC) 降解剂,化合物10 (MS8709),有效降解这些致癌酶. 这种新型治疗方法在治疗依赖G9a/GLP活性的癌症方面表现有前途.

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:

氨基甲基转移酶G9a和GLP的异常表达与癌症的发展有关.
G9a/GLP表现出催化和非催化瘤功能.
现有的G9a/GLP催化抑制剂对抗癌疗效有限.

研究的目的:

发现和描述一流的G9a/GLP蛋白质分解向化母 (PROTAC) 降解剂.
评估这一新型PROTAC作为抗癌治疗药物的潜力.

主要方法:

开发一个针对G9a/GLP的PROTAC (组合10,MS8709).
评估化合物10的降解活性,选择性和机制 (ubiquitin-proteasome系统).
评估化合物10在各种癌症类型中抑制癌细胞生长的疗效.
在小鼠中的药理动力学研究.

主要成果:

化合物10以剂量,时间和UPS依赖的方式诱导G9a/GLP降解.
化合物10对G9a/GLP具有选择性,不会影响它们的mRNA水平.
与母抑制剂UNC0642相比,化合物10在前列腺,白血病和肺癌细胞中表现出优异的细胞生长抑制.
化合物10在体内研究中表现出适合的药理动力学特性.

结论:

化合物10是一种新的G9a/GLP PROTAC降解剂,具有显著的抗癌潜力.
这种降解剂作为一种有价值的化学生物学工具,用于研究G9a/GLP功能.
化合物10为G9a/GLP依赖性癌症提供了一个有前途的治疗策略.

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