死亡相关蛋白激酶1 PROTACs的设计、合成和生物学评价。

IF 4.7 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic Chemistry Pub Date : 2025-09-28 DOI:10.1016/j.bioorg.2025.109044

Xueyin Wu, Ruomeng Li, Wujin Tian, Jing Yao, Dongmei Chen, Tae Ho Lee, Yang Liu

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引用次数: 0

摘要

死亡相关蛋白激酶1 （DAPK1）是细胞自噬和细胞凋亡的重要调控因子。DAPK1与癌症和各种神经退行性疾病密切相关。神经退行性疾病是一种以神经元功能和结构逐渐丧失为特征的慢性进行性疾病。尽管正在进行研究，但目前还没有有效的治疗方法，需要进一步的研究。新出现的蛋白水解靶向嵌合体（PROteolysis TArgeting Chimeras, PROTACs）策略具有高效能和广泛靶点覆盖的特点，可能代表着一种有前景的治疗发展途径。本文介绍了靶向DAPK1的PROTACs的设计、合成和生物学评价。最有希望的化合物CP1可以在较低浓度（DC50 = 0.1196 μM）下持续有效地降解DAPK1。总的来说，我们的化合物CP1在降解DAPK1方面表现出很强的功效，并显示出治疗神经元细胞死亡的潜力。

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Design, synthesis, and biological evaluation of death-associated protein kinase 1 PROTACs.

Death-associated protein kinase 1 (DAPK1) serves as a crucial regulator of both autophagy and apoptosis. DAPK1 has been closely linked to cancer and various neurodegenerative diseases. Neurodegenerative disorders are chronic and progressive conditions characterized by the gradual loss of neuronal function and structure. Despite ongoing research, no effective cure currently exists, and further studies are needed. The emerging PROteolysis TArgeting Chimeras (PROTACs) strategy, characterized by high potency and broad target coverage, may represent a promising avenue for therapeutic development. Here we describe the design, synthesis, and biological evaluation of first-in-class PROTACs targeting DAPK1. The compound with the most promising results, CP1, can achieve sustained and effective degradation of DAPK1 at a relatively low concentration (DC₅₀ = 0.1196 μM). Overall, our compound CP1 demonstrated strong efficacy in degrading DAPK1 and shows potential for treating neuronal cell death.

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来源期刊

Bioorganic Chemistry 生物-生化与分子生物学

CiteScore

9.70

自引率

3.90%

发文量

679

审稿时长

31 days

期刊介绍： Bioorganic Chemistry publishes research that addresses biological questions at the molecular level, using organic chemistry and principles of physical organic chemistry. The scope of the journal covers a range of topics at the organic chemistry-biology interface, including: enzyme catalysis, biotransformation and enzyme inhibition; nucleic acids chemistry; medicinal chemistry; natural product chemistry, natural product synthesis and natural product biosynthesis; antimicrobial agents; lipid and peptide chemistry; biophysical chemistry; biological probes; bio-orthogonal chemistry and biomimetic chemistry. For manuscripts dealing with synthetic bioactive compounds, the Journal requires that the molecular target of the compounds described must be known, and must be demonstrated experimentally in the manuscript. For studies involving natural products, if the molecular target is unknown, some data beyond simple cell-based toxicity studies to provide insight into the mechanism of action is required. Studies supported by molecular docking are welcome, but must be supported by experimental data. The Journal does not consider manuscripts that are purely theoretical or computational in nature. The Journal publishes regular articles, short communications and reviews. Reviews are normally invited by Editors or Editorial Board members. Authors of unsolicited reviews should first contact an Editor or Editorial Board member to determine whether the proposed article is within the scope of the Journal.