Discovery of novel 5-phenyl-1H-pyrrole-2-carboxylic acids as Keap1-Nrf2 inhibitors for acute lung injury treatment

IF 4.5 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Bioorganic Chemistry Pub Date : 2024-08-31 DOI:10.1016/j.bioorg.2024.107741

{"title":"Discovery of novel 5-phenyl-1H-pyrrole-2-carboxylic acids as Keap1-Nrf2 inhibitors for acute lung injury treatment","authors":"","doi":"10.1016/j.bioorg.2024.107741","DOIUrl":null,"url":null,"abstract":"<div>Oxidative stress is intricately linked to acute lung injury (ALI) and cerebral ischemic/reperfusion (I/R) injury. The Keap1 (Kelch-like ECH-Associating protein 1)-Nrf2 (nuclear factor erythroid 2-related factor 2)-ARE (antioxidant response element) signaling pathway, recognized as a crucial regulatory mechanism in oxidative stress, holds immense potential for the treatment of both diseases. In our laboratory, we initially screened a compound library and identified compound 3, which exhibited a dissociation constant of 5090 nM for Keap1. To enhance its binding affinity, we developed a novel 5-phenyl-1H-pyrrole-2-carboxylic acid Keap1-Nrf2 inhibitor through scaffold hopping from compound 3. Structure-activity relationship studies identified compound 19 as the most potent, with a KD2 of 42.2 nM against Keap1. Furthermore, compound 19 showed significant protection against LPS-induced injury in BEAS-2B cells and promoted Nrf2 nuclear translocation. Subsequently, we investigated its therapeutic effects in mouse models of ALI injury. Compound 19 effectively alleviated symptoms at doses of 15 mg/kg for ALI injury. Additionally, it facilitated Nrf2 translocation to the nucleus, increased Nrf2 levels, and upregulated the expression of HO-1 and NQO1 in affected tissues.</div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":null,"pages":null},"PeriodicalIF":4.5000,"publicationDate":"2024-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Bioorganic Chemistry","FirstCategoryId":"92","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0045206824006461","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Oxidative stress is intricately linked to acute lung injury (ALI) and cerebral ischemic/reperfusion (I/R) injury. The Keap1 (Kelch-like ECH-Associating protein 1)-Nrf2 (nuclear factor erythroid 2-related factor 2)-ARE (antioxidant response element) signaling pathway, recognized as a crucial regulatory mechanism in oxidative stress, holds immense potential for the treatment of both diseases. In our laboratory, we initially screened a compound library and identified compound 3, which exhibited a dissociation constant of 5090 nM for Keap1. To enhance its binding affinity, we developed a novel 5-phenyl-1H-pyrrole-2-carboxylic acid Keap1-Nrf2 inhibitor through scaffold hopping from compound 3. Structure-activity relationship studies identified compound 19 as the most potent, with a K_D2 of 42.2 nM against Keap1. Furthermore, compound 19 showed significant protection against LPS-induced injury in BEAS-2B cells and promoted Nrf2 nuclear translocation. Subsequently, we investigated its therapeutic effects in mouse models of ALI injury. Compound 19 effectively alleviated symptoms at doses of 15 mg/kg for ALI injury. Additionally, it facilitated Nrf2 translocation to the nucleus, increased Nrf2 levels, and upregulated the expression of HO-1 and NQO1 in affected tissues.

Abstract Image

查看原文

微信好友朋友圈 QQ好友复制链接

本刊更多论文

发现治疗急性肺损伤的新型 5-苯基-1H-吡咯-2-羧酸 Keap1-Nrf2 抑制剂

氧化应激与急性肺损伤（ALI）和脑缺血再灌注损伤（I/R）密切相关。Keap1（Kelch-like ECH-Associating protein 1）-Nrf2（核因子红细胞2相关因子2）-ARE（抗氧化反应元件）信号通路被认为是氧化应激的关键调控机制，在治疗这两种疾病方面具有巨大潜力。我们实验室最初筛选了一个化合物库，发现了化合物 3，它与 Keap1 的解离常数为 5090 nM。为了增强其结合亲和力，我们通过化合物 3 的支架跳跃开发出了一种新型 5-苯基-1H-吡咯-2-羧酸 Keap1-Nrf2 抑制剂。通过结构-活性关系研究发现，化合物 19 的药效最强，对 Keap1 的 KD2 为 42.2 nM。此外，化合物 19 对 LPS 诱导的 BEAS-2B 细胞损伤具有显著的保护作用，并能促进 Nrf2 的核转位。随后，我们研究了化合物 19 在 ALI 损伤小鼠模型中的治疗效果。当剂量为 15 mg/kg 时，化合物 19 能有效缓解 ALI 损伤症状。此外，它还能促进 Nrf2 转位至细胞核，提高 Nrf2 水平，并上调受影响组织中 HO-1 和 NQO1 的表达。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文去求助

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.