Yim Hyerin, Sun Renhong, Xu Zhongli, Kim Huen Suk, Kim Minjeong, Cao Tao, Xie Ling, Chen Xian, Kaniskan H Ümit, Jin Jian
Mount 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.
Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, United States.
Eur J Med Chem. 2025 Jul 5;291:117595. doi: 10.1016/j.ejmech.2025.117595. Epub 2025 Apr 2.
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.
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具有与其甲基转移酶活性无关的生物学功能。因此，利用蛋白酶靶向嵌合体（PROTAC）靶向并降解DOT1L可能是一种有前景的治疗策略。在此，我们报告了首个一流的DOT1L PROTAC降解剂化合物13（MS2133）的发现，它能以浓度和时间依赖性方式有效诱导DOT1L降解，且不影响DOT1L mRNA表达。化合物13诱导的DOT1L降解需要与E3连接酶希佩尔-林道（VHL）和DOT1L结合，并通过泛素-蛋白酶体系统发生。化合物13对DOT1L的选择性高于其他甲基转移酶，能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。总体而言，化合物13是进一步研究DOT1L功能的有价值的化学生物学工具，也是治疗DOT1L依赖性癌症的潜在药物。
