Design and synthesis of JNK1-targeted PROTACs and research on the activity.

IF 4.5 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic Chemistry Pub Date : 2025-01-01 Epub Date: 2024-12-15 DOI:10.1016/j.bioorg.2024.108044

Yue Guo, Fengling Liu, Man Chi, Hewen Qian, Ye Zhang, Yaxia Yuan, Shurong Hou, Xiabin Chen, Lei Ma

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引用次数: 0

Abstract

Kinase dysregulation is greatly associated with cell growth, proliferation, differentiation and apoptosis, which indicates their great potential as therapeutic targets for treatment of numerous progressive disorders, including inflammatory, metabolic and autoimmune disorders, organ fibrosis and cancer. The c‑Jun N‑Terminal Kinase (JNK), as a member of MAPK family, is proved to be a potential target for the treatment of pulmonary fibrosis, which is the most common progressive and fatal fibrotic lung disease. As a new strategy, small-molecule-mediated targeted protein degradation pathway has the advantages of catalytic properties, overcoming drug resistance and expanding target space, which can circumvent the limitations associated with kinase inhibitors. Proteolysis targeting chimeras (PROTAC) contains a linker to concatenate a ligand of E3 ubiquitin ligase and a ligand for a protein of interest (POI). We developed a total of 20 JNK1-targeted PROTACs that induce proteasomal degradation of JNK1 components. The most active PROTAC molecule PA2 was then investigated by JNK1 enzyme assay and protein degradation assay, which suggested that PA2 had an anti-JNK1 ability and provided insights for the future use of JNK1-targeted PROTAC as treatment drugs for pulmonary fibrosis.

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jnk1靶向PROTACs的设计合成及活性研究。

激酶失调与细胞生长、增殖、分化和凋亡密切相关，这表明它们作为治疗许多进行性疾病（包括炎症、代谢和自身免疫性疾病、器官纤维化和癌症）的治疗靶点具有巨大潜力。c - Jun N -末端激酶（JNK）作为MAPK家族的成员，被证明是治疗肺纤维化的潜在靶点，肺纤维化是最常见的进行性和致死性纤维化肺疾病。小分子介导的靶向蛋白降解途径作为一种新的策略，具有催化特性、克服耐药、扩大靶标空间等优点，可以规避激酶抑制剂的局限性。蛋白水解靶向嵌合体（PROTAC）包含连接E3泛素连接酶配体和感兴趣蛋白（POI）配体的连接体。我们共开发了20种靶向JNK1的PROTACs，可诱导JNK1成分的蛋白酶体降解。然后通过JNK1酶测定和蛋白质降解试验研究了最活跃的PROTAC分子PA2，这表明PA2具有抗JNK1能力，并为未来使用JNK1靶向PROTAC作为肺纤维化治疗药物提供了见解。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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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.