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

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

  • Bioorg Chem. 2024 Jul:148:107481. 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
Affiliations

Affiliations

  • 1 Department of Applied Chemistry, Dongduk Women's University, Seoul 02748, Republic of Korea.
  • 2 Department of Biological Sciences, Konkuk University, Seoul 05029, Republic of Korea.
  • 3 Division of Bioscience and Biotechnology, BMIC, Konkuk University, Seoul 05029, Republic of Korea.
  • 4 Department of Biological Sciences, Konkuk University, Seoul 05029, Republic of Korea; Cancer and Metabolism Institute, Konkuk University, Seoul 05029, Republic of Korea. Electronic address: shinsy@konkuk.ac.kr.
Abstract

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 (IT21, IT23, and IT25) were identified as novel inhibitors of EGR-1 DNA-binding activity. In silico 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, IT21, IT23, and IT25 effectively reduced mRNA expression of TNFα-induced EGR-1-regulated inflammatory genes, particularly in HaCaT keratinocytes inflamed by TNFα. In the in vivo efficacy study, IT21, IT23, and IT25 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 (IT21, IT23, and IT25) could serve as lead compounds for the development of potential therapeutic agents against inflammatory skin disorders, including atopic dermatitis.

Keywords

2-(2-Oxoindolin-3-ylidene)hydrazinecarbothioamides; Atopic dermatitis; DNA-binding activity; EGR-1; Molecular docking.

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