Discovery of the first-in-class DOT1L PROTAC degrader

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry Pub Date : 2025-04-02 DOI:10.1016/j.ejmech.2025.117595

Hyerin Yim , Renhong Sun , Zhongli Xu , Huen Suk Kim , Minjeong Kim , Tao Cao , Ling Xie , Xian Chen , H. Ümit Kaniskan , Jian Jin

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引用次数: 0

Abstract

DOT1L is the lysine methyltransferase responsible for histone H3 lysine 79 (H3K79) methylation and plays a crucial role in leukemia progression. Furthermore, DOT1L has biological functions that are independent of its methyltransferase activity. Therefore, targeting and degrading DOT1L with PROteolysis TArgeting Chimeras (PROTACs) could represent a promising therapeutic strategy. Here, we report the discovery of the first-in-class DOT1L PROTAC degrader, compound 13 (MS2133), which potently induces DOT1L degradation in a concentration- and time-dependent manner, without affecting DOT1L mRNA expression. The DOT1L degradation induced by 13 requires binding to the E3 ligase von Hippel-Lindau (VHL) and DOT1L and occurs through the ubiquitin-proteasome system. 13 is selective for DOT1L over other methyltransferases and effectively inhibits the growth of mixed lineage leukemia-rearranged (MLL-r) leukemia cells while having no toxicity on normal cells. Overall, 13 is a valuable chemical biology tool for further studying functions of DOT1L and a potential therapeutic for DOT1L-dependent cancers.

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发现一流的 DOT1L PROTAC 降解剂

DOT1L是负责组蛋白H3赖氨酸79 （H3K79）甲基化的赖氨酸甲基转移酶，在白血病进展中起关键作用。此外，DOT1L具有独立于其甲基转移酶活性的生物学功能。因此，用蛋白水解靶向嵌合体（PROteolysis targeting Chimeras, PROTACs）靶向和降解DOT1L可能是一种很有前景的治疗策略。在这里，我们报告了同类中首个DOT1L PROTAC降解物化合物13 （MS2133）的发现，它以浓度和时间依赖的方式有效地诱导DOT1L降解，而不影响DOT1L mRNA的表达。13诱导的DOT1L降解需要结合E3连接酶von Hippel-Lindau （VHL）和DOT1L，并通过泛素-蛋白酶体系统发生。与其他甲基转移酶相比，13对DOT1L具有选择性，可有效抑制混合谱系白血病-重排（MLL-r）白血病细胞的生长，同时对正常细胞无毒性。综上所述，13是进一步研究DOT1L功能和治疗DOT1L依赖性癌症的一个有价值的化学生物学工具。

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来源期刊

European Journal of Medicinal Chemistry 化学-医药化学

CiteScore

11.70

自引率

9.00%

发文量

863

审稿时长

29 days

期刊介绍： The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers. A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.