Discovery of a doublecortin-like kinase 1 inhibitor to prevent inflammatory responses in acute lung injury
Copyright © 2024 Elsevier Inc. All rights reserved..
Doublecortin-like kinase 1 (DCLK1) is a microtubule-associated protein kinase involved in neurogenesis and human cancer. Recent studies have revealed a novel functional role for DCLK1 in inflammatory signaling, thus positioning it as a novel target kinase for respiratory inflammatory disease treatment. In this study, we designed and synthesized a series of NVP-TAE684-based derivatives as novel anti-inflammatory agents targeting DCLK1. Bio-layer interferometry binding screening and kinase assays of the NVP-TAE684 derivatives led to the discovery of an effective DCLK1 inhibitor (a24), with an IC50 of 179.7 nM. Compound a24 effectively inhibited lipopolysaccharide (LPS)-induced inflammation in macrophages with higher potency than the lead compound. Mechanistically, compound a24 inhibited LPS-induced inflammation by inhibiting DCLK1-mediated IKKβ phosphorylation. Furthermore, compound a24 showed in vivo anti-inflammatory activity in an LPS-challenged acute lung injury model. These findings suggest that compound a24 may serve as a novel candidate for the development of DCLK1 inhibitors and a potential therapeutic agent for the treatment of inflammatory diseases.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:145 |
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| Enthalten in: |
Bioorganic chemistry - 145(2024) vom: 05. März, Seite 107215 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Cai, Binhao [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 15.03.2024 Date Revised 15.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.bioorg.2024.107215 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM368849015 |
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| 520 | |a Doublecortin-like kinase 1 (DCLK1) is a microtubule-associated protein kinase involved in neurogenesis and human cancer. Recent studies have revealed a novel functional role for DCLK1 in inflammatory signaling, thus positioning it as a novel target kinase for respiratory inflammatory disease treatment. In this study, we designed and synthesized a series of NVP-TAE684-based derivatives as novel anti-inflammatory agents targeting DCLK1. Bio-layer interferometry binding screening and kinase assays of the NVP-TAE684 derivatives led to the discovery of an effective DCLK1 inhibitor (a24), with an IC50 of 179.7 nM. Compound a24 effectively inhibited lipopolysaccharide (LPS)-induced inflammation in macrophages with higher potency than the lead compound. Mechanistically, compound a24 inhibited LPS-induced inflammation by inhibiting DCLK1-mediated IKKβ phosphorylation. Furthermore, compound a24 showed in vivo anti-inflammatory activity in an LPS-challenged acute lung injury model. These findings suggest that compound a24 may serve as a novel candidate for the development of DCLK1 inhibitors and a potential therapeutic agent for the treatment of inflammatory diseases | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Acute lung injury | |
| 650 | 4 | |a Anti-inflammatory | |
| 650 | 4 | |a Doublecortin-like kinase 1 | |
| 650 | 4 | |a Drug design | |
| 650 | 7 | |a Doublecortin-Like Kinases |2 NLM | |
| 650 | 7 | |a EC 2.7.1.11 |2 NLM | |
| 650 | 7 | |a Intracellular Signaling Peptides and Proteins |2 NLM | |
| 650 | 7 | |a Lipopolysaccharides |2 NLM | |
| 650 | 7 | |a Protein Serine-Threonine Kinases |2 NLM | |
| 650 | 7 | |a EC 2.7.11.1 |2 NLM | |
| 650 | 7 | |a DCLK1 protein, human |2 NLM | |
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| 700 | 1 | |a Xu, Ying |e verfasserin |4 aut | |
| 700 | 1 | |a Luo, Ruixiang |e verfasserin |4 aut | |
| 700 | 1 | |a Lu, Kongqin |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Yuhan |e verfasserin |4 aut | |
| 700 | 1 | |a Zheng, Lei |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Yawen |e verfasserin |4 aut | |
| 700 | 1 | |a Yin, Lina |e verfasserin |4 aut | |
| 700 | 1 | |a Tu, Linglan |e verfasserin |4 aut | |
| 700 | 1 | |a Luo, Wu |e verfasserin |4 aut | |
| 700 | 1 | |a Zheng, Lulu |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Fengzhi |e verfasserin |4 aut | |
| 700 | 1 | |a Lv, Xinting |e verfasserin |4 aut | |
| 700 | 1 | |a Tang, Qidong |e verfasserin |4 aut | |
| 700 | 1 | |a Liang, Guang |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Lingfeng |e verfasserin |4 aut | |
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