Design, synthesis, and biological evaluation of 2-(2-oxoindolin-3-ylidene)hydrazinecarbothioamides as a potential EGR-1 inhibitor for targeted therapy of atopic dermatitis,Bioorganic Chemistry

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Design, synthesis, and biological evaluation of 2-(2-oxoindolin-3-ylidene)hydrazinecarbothioamides as a potential EGR-1 inhibitor for targeted therapy of atopic dermatitis
Bioorganic Chemistry ( IF 4.5 ) Pub Date : 2024-05-21 , DOI: 10.1016/j.bioorg.2024.107481
Seunghyun Ahn ₁ , Hyunjin Yeo ₂ , Euitaek Jung ₂ , Youngshim Lee ₃ , Dongsoo Koh ₁ , Hyeonhwa Lee ₁ , Young Han Lee ₂ , Yoongho Lim ₃ , Soon Young Shin ₄

Affiliation

Atopic dermatitis is a chronic inflammatory skin disease characterized by intense itching and frequent skin barrier dysfunctions. EGR-1 is a transcription factor that aggravates the pathogenesis of atopic dermatitis by promoting the production of various inflammatory cytokines. Three 2-(2-oxoindolin-3-ylidene)hydrazinecarbothioamides (, , and ) were identified as novel inhibitors of EGR-1 DNA-binding activity. docking experiments were performed to elucidate the binding conditions of the EGR-1 zinc-finger (ZnF) DNA-binding domain. Electrophoretic mobility shift assays confirmed the targeted binding effect on the EGR-1 ZnF DNA-binding domain, leading to dose-dependent dissociation of the EGR-1–DNA complex. At the functional cellular level, , , and effectively reduced mRNA expression of TNFα-induced EGR-1-regulated inflammatory genes, particularly in HaCaT keratinocytes inflamed by TNFα. In the efficacy study, , , and demonstrated the potential to alleviate atopic dermatitis-like skin lesions in the ear skin of BALB/c mice. These findings suggest that targeting the EGR-1 ZnF DNA-binding domain with 2-(2-oxoindolin-3-ylidene)hydrazinecarbothioamide derivatives (, , and could serve as lead compounds for the development of potential therapeutic agents against inflammatory skin disorders, including atopic dermatitis.

中文翻译：

2-(2-氧吲哚啉-3-亚基)肼硫碳酰胺的设计、合成和生物学评价作为潜在的 EGR-1 抑制剂，用于特应性皮炎的靶向治疗

特应性皮炎是一种慢性炎症性皮肤病，其特征是剧烈瘙痒和频繁的皮肤屏障功能障碍。 EGR-1是一种转录因子，通过促进多种炎症细胞因子的产生而加重特应性皮炎的发病机制。三种 2-(2-氧吲哚啉-3-亚基)肼硫碳酰胺 (、、和) 被鉴定为 EGR-1 DNA 结合活性的新型抑制剂。进行对接实验以阐明 EGR-1 锌指 (ZnF) DNA 结合结构域的结合条件。电泳迁移率变动测定证实了对 EGR-1 ZnF DNA 结合域的靶向结合作用，导致 EGR-1-DNA 复合物发生剂量依赖性解离。在功能细胞水平上，、、和有效降低 TNFα 诱导的 EGR-1 调节炎症基因的 mRNA 表达，特别是在 TNFα 炎症的 HaCaT 角质形成细胞中。在功效研究中，、、和展示了缓解 BALB/c 小鼠耳部皮肤中特应性皮炎样皮肤病变的潜力。这些发现表明，用 2-(2-氧吲哚啉-3-亚基)肼硫代甲酰胺衍生物（、、和）靶向 EGR-1 ZnF DNA 结合结构域可以作为先导化合物，用于开发针对炎症性皮肤病的潜在治疗剂，包括特应性皮炎。

更新日期：2024-05-21

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