1. Discovery of a doublecortin-like kinase 1 inhibitor to prevent inflammatory responses in acute lung injury.
- Author
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Cai B, Xu Y, Luo R, Lu K, Wang Y, Zheng L, Zhang Y, Yin L, Tu L, Luo W, Zheng L, Zhang F, Lv X, Tang Q, Liang G, and Chen L
- Subjects
- Humans, Intracellular Signaling Peptides and Proteins, Lipopolysaccharides pharmacology, Protein Serine-Threonine Kinases, Inflammation drug therapy, Doublecortin-Like Kinases, Acute Lung Injury chemically induced, Acute Lung Injury drug therapy
- Abstract
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 IC
50 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., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Lingfeng Chen reports financial support was provided by National Natural Science Foundation of China. Lingfeng Chen reports financial support was provided by Natural Science Funding of Zhejiang Province. Guang Liang reports financial support was provided by Zhejiang Provincial Key Scientific Project. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)- Published
- 2024
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