Hosseini Amir, Qiu Xing, Xiong Yan, Chiang Ki Him Nicholas, Catlett Jerrel, Kaltheuner Ines, Deng Zhijie, Ghosh Sudipta, Shi Yang, Jin Jian
Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom.
Mount Sinai Center for Therapeutics Discovery, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
Proc Natl Acad Sci U S A. 2025 May 20;122(20):e2425812122. doi: 10.1073/pnas.2425812122. Epub 2025 May 14.
Aberrant expression of lysine-specific demethylase 1 (LSD1) has been implicated in various cancers, including acute myeloid leukemia (AML). Recent studies have revealed both catalytic and noncatalytic oncogenic functions of LSD1, which cannot be effectively addressed by traditional small-molecule inhibitors. Therefore, to remove LSD1 and mitigate its oncogenic activity, we utilized the proteolysis-targeting chimera (PROTAC) approach and developed an LSD1 PROTAC degrader MS9117, which recruits the E3 ligase cereblon (CRBN). MS9117 induces LSD1 degradation in a concentration-, time-, CRBN-, and proteasome-dependent manner. Importantly, MS9117 effectively degrades LSD1 and demonstrates superior antiproliferative effects in AML cells, compared to the existing pharmacological LSD1 inhibitors. Furthermore, MS9117 also sensitized nonacute promyelocytic leukemia AML cells to all-trans retinoic acid treatment. Moreover, we developed two negative controls of MS9117, MS9117N1 and MS9117N2, which do not degrade LSD1 or inhibit leukemia cell growth, further confirming the mechanism of action of MS9117. Overall, MS9117 serves as a valuable chemical tool and a potential therapeutic to target both the catalytic and scaffolding functions of LSD1. With several LSD1 inhibitors already in clinical development, the LSD1 degraders such as MS9117 offer an additional option for future clinical studies.
赖氨酸特异性去甲基化酶1（LSD1）的异常表达与包括急性髓系白血病（AML）在内的多种癌症有关。最近的研究揭示了LSD1的催化和非催化致癌功能，而传统的小分子抑制剂无法有效解决这些问题。因此，为了去除LSD1并减轻其致癌活性，我们采用了蛋白酶靶向嵌合体（PROTAC）方法，开发了一种LSD1 PROTAC降解剂MS9117，它能募集E3连接酶cereblon（CRBN）。MS9117以浓度、时间、CRBN和蛋白酶体依赖性方式诱导LSD1降解。重要的是，与现有的LSD1药理学抑制剂相比，MS9117能有效降解LSD1，并在AML细胞中表现出卓越的抗增殖作用。此外，MS9117还使非急性早幼粒细胞白血病AML细胞对全反式维甲酸治疗敏感。此外，我们还开发了MS9117的两个阴性对照MS9117N1和MS9117N2，它们不会降解LSD1或抑制白血病细胞生长，进一步证实了MS9117的作用机制。总体而言，MS9117是一种有价值的化学工具，也是一种潜在的治疗药物，可靶向LSD1的催化和支架功能。鉴于已有几种LSD1抑制剂正在进行临床开发，像MS9117这样的LSD1降解剂为未来的临床研究提供了额外的选择。
