Division of Chemical Engineering, Konkuk University, Seoul 05029, Republic of Korea.
Department of Applied Chemistry, Dongduk Women's University, Seoul 02748, Republic of Korea.
Bioorg Med Chem Lett. 2024 Nov 15;113:129952. doi: 10.1016/j.bmcl.2024.129952. Epub 2024 Sep 10.
To identify compounds inhibiting the activity of the Early Growth Response (EGR)-1 DNA-binding domain, thirty-seven pyrazolines were prepared and their EGR-1 DNA-binding activities were measured. Pharmacophores were derived based on quantitative structure-activity relationship calculations. As compound 2, 1-(5-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-3-yl)naphthalen-2-ol, showed the best inhibitory effects against the activity of the EGR-1 DNA-binding domain, the binding mode between compound 2 and EGR-1 was elucidated using in silico docking. The pharmacophores were matched to the binding modes. Electrophoretic mobility shift assays confirmed that compound 2 dose-dependently inhibited TNFα-induced EGR-1-DNA complex formation in HaCaT cells. Reverse transcription-polymerase chain reaction demonstrated that compound 2 effectively reduced the mRNA expression of EGR-1-regulated inflammatory genes, including thymic stromal lymphopoietin (TSLP), interleukin (IL)-1β, IL-6, and IL-31, in TNFα-stimulated HaCaT cells. Therefore, compound 2 could be developed as an agent that inhibits the activity of the EGR-1 DNA-binding domain.
为了鉴定抑制早期生长反应（EGR）-1 DNA 结合域活性的化合物，合成了 37 种吡唑啉类化合物，并测定了它们对 EGR-1 DNA 结合活性的影响。基于定量构效关系计算，推导出了药效团。化合物 2，1-（5-（4-甲氧基苯基）-4,5-二氢-1H-吡唑-3-基）萘-2-醇，对 EGR-1 DNA 结合域的活性抑制作用最强，利用计算机对接阐明了化合物 2 与 EGR-1 之间的结合模式。药效团与结合模式相匹配。电泳迁移率变动分析证实，化合物 2 可剂量依赖性地抑制 TNFα 诱导的 HaCaT 细胞中 EGR-1-DNA 复合物的形成。逆转录-聚合酶链反应表明，化合物 2 可有效降低 TNFα 刺激的 HaCaT 细胞中 EGR-1 调节的炎症基因，包括胸腺基质淋巴细胞生成素（TSLP）、白细胞介素（IL）-1β、IL-6 和 IL-31 的 mRNA 表达。因此，化合物 2 可被开发为抑制 EGR-1 DNA 结合域活性的药物。
