发现 KW0113 是首个有效的 DNMT1 蛋白 PROTAC 降解剂

IF 3.6 4区医学 Q2 CHEMISTRY, MEDICINAL

ChemMedChem Pub Date : 2024-09-20 DOI:10.1002/cmdc.202400467

Huihui Wang, Zhaoliang Wang, Linghao Hu, Bingjie Yang, Liangyi Zong, Dounan Xu, Bo Yu, Xiangqian Kong, Mingliang Wang

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引用次数: 0

摘要

DNA 甲基转移酶 1（DNMT1）是治疗急性髓细胞白血病（AML）和其他恶性肿瘤的一个极具吸引力的靶点。据报道，通过逆转 DNA 甲基化异常，遗传性去掉 DNMT1 可抑制 AML 细胞增殖。然而，目前还没有关于 DNMT1 靶向 PROTAC 降解剂的报道。在此，我们开发了一系列基于双氰基吡啶支架和 VHL E3 泛素连接酶配体的 DNMT1 蛋白分解靶向嵌合体（PROTAC）降解剂。其中，KW0113（在 MV4-11/MOLM-13 细胞中的 DC50 = 643/899 nM）表现出最佳的 DNMT1 降解效果。KW0113 通过 VHL 参与，以剂量和时间依赖的方式诱导 DNMT1 选择性降解。此外，KW0113还能通过逆转启动子DNA高甲基化和肿瘤抑制基因沉默来抑制AML细胞的生长。总之，这些发现证明了 PROTAC 策略诱导 DNMT1 降解的能力，展示了 DNMT1 靶向 PROTACs 的治疗潜力。这项工作还为 DNMT1 相关研究提供了一种便捷的化学敲除工具。

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Discovery of KW0113 as a First and Effective PROTAC Degrader of DNMT1 Protein

DNA methyltransferase 1 (DNMT1) is an attractive therapeutic target for acute myelocytic leukemia (AML) and other malignancies. It has been reported that the genetic depletion of DNMT1 inhibited AML cell proliferation through reversing DNA methylation abnormalities. However, no DNMT1-targeted PROTAC degraders have been reported yet. Herein, a series of proteolysis-targeting chimera (PROTAC) degrader of DNMT1 based on dicyanopyridine scaffold and VHL E3 ubiquitin ligase ligand was developed. Among them, KW0113 (DC50 = 643/899 nM in MV4-11/MOLM-13 cells) exhibited optimal DNMT1 degradation. KW0113 induced DNMT1-selective degradation in a dose- and time-dependent manner through VHL engagement. Moreover, KW0113 inhibited AML cell growth by reversing promoter DNA hypermethylation and tumor-suppressor genes silencing. In conclusion, these findings proved the capability of PROTAC strategy for inducing DNMT1 degradation, demonstrated the therapeutic potential of DNMT1-targeted PROTACs. This work also provided a convenient chemical knockdown tool for DNMT1-related studies.

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来源期刊

ChemMedChem 医学-药学

CiteScore

6.70

自引率

2.90%

发文量

280

审稿时长

1 months

期刊介绍： Quality research. Outstanding publications. With an impact factor of 3.124 (2019), ChemMedChem is a top journal for research at the interface of chemistry, biology and medicine. It is published on behalf of Chemistry Europe, an association of 16 European chemical societies. ChemMedChem publishes primary as well as critical secondary and tertiary information from authors across and for the world. Its mission is to integrate the wide and flourishing field of medicinal and pharmaceutical sciences, ranging from drug design and discovery to drug development and delivery, from molecular modeling to combinatorial chemistry, from target validation to lead generation and ADMET studies. ChemMedChem typically covers topics on small molecules, therapeutic macromolecules, peptides, peptidomimetics, and aptamers, protein-drug conjugates, nucleic acid therapies, and beginning 2017, nanomedicine, particularly 1) targeted nanodelivery, 2) theranostic nanoparticles, and 3) nanodrugs. Contents ChemMedChem publishes an attractive mixture of: Full Papers and Communications Reviews and Minireviews Patent Reviews Highlights and Concepts Book and Multimedia Reviews.