发现了第一类DOT1L PROTAC降解器
Hyerin Yim1, Renhong Sun1, Zhongli Xu1
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, NY, 10029, United States.
European journal of medicinal chemistry
|April 5, 2025
概括
我们开发了一种新的PROTAC降解剂,化合物13 (MS2133),它有效地准和降解DOT1L,这是白血病进展中的关键蛋白质. 这种有针对性的方法显示出治疗DOT1L-依赖癌症而不会损害正常细胞的前景.
科学领域:
- 生物化学 生化学
- 分子生物学分子生物学
- 癌症治疗方法 癌症治疗方法
背景情况:
- DOT1L是H3K79甲基化中的关键基因组甲基转移酶,涉及到白血病的进展.
- DOT1L表现出超出其甲基转移酶活性的生物功能,表明更广泛的治疗潜力.
研究的目的:
- 发现和描述为DOT1L.第一个类型中的PROTEOLYSIS TARGETING CHIMERA (PROTAC) 降解剂.
- 评估DOT1L降解在混合血统白血病重组 (MLL-r) 白血病中的治疗潜力.
主要方法:
- 作为DOT1L PROTAC降解剂的化合物13 (MS2133) 的开发.
- 通过无素-蛋白酶系统评估DOT1L降解,需要VHL E3酶结合.
- 对MLL-r白血病细胞和正常细胞中13化合物的选择性和疗效的评估.
主要成果:
- 化合物13强烈而选择性地诱导DOT1L降解,时间和度取决于这种方式.
- 降解通过VHL E3结合酶和无素-蛋白酶系统进行介导,独立于DOT1LmRNA水平.
- 化合物13有效抑制MLL-r白血病细胞生长,在正常细胞中没有观察到毒性.
结论:
- 化合物13是第一类DOT1L PROTAC降解剂,对DOT1L依赖性癌症具有显著的治疗潜力.
- 这种化学探测器是进一步阐明DOT1L生物功能的宝贵工具.
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