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  3. Discovery of a doublecortin-like kinase 1 inhibitor to prevent inflammatory responses in acute lung injury

Discovery of a doublecortin-like kinase 1 inhibitor to prevent inflammatory responses in acute lung injury

  • Bioorg Chem. 2024 Apr:145:107215. doi: 10.1016/j.bioorg.2024.107215.
Binhao Cai 1,  Ying Xu 2,  Ruixiang Luo 2,  Kongqin Lu 3,  Yuhan Wang 2,  Lei Zheng 2,  Yawen Zhang 2,  Lina Yin 2,  Linglan Tu 2,  Wu Luo 4,  Lulu Zheng 5,  Fengzhi Zhang 2,  Xinting Lv 2,  Qidong Tang 6,  Guang Liang 7,  Lingfeng Chen 8
Affiliations

Affiliations

  • 1 Department of Pharmacy and Institute of Inflammation, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310014, China; School of Pharmacy, Hangzhou Medical College, Hangzhou 310012 Zhejiang, China; Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
  • 2 School of Pharmacy, Hangzhou Medical College, Hangzhou 310012 Zhejiang, China.
  • 3 Schol of Basic Medicine, Inner Mongolia Medical University, Hohhot 010059, China.
  • 4 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
  • 5 Department of Pharmacy, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang 310000, China.
  • 6 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address: tangqidongcn@126.com.
  • 7 Department of Pharmacy and Institute of Inflammation, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310014, China; School of Pharmacy, Hangzhou Medical College, Hangzhou 310012 Zhejiang, China; Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address: wzmcliangguang@163.com.
  • 8 Department of Pharmacy and Institute of Inflammation, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310014, China; School of Pharmacy, Hangzhou Medical College, Hangzhou 310012 Zhejiang, China. Electronic address: lfchen@hmc.edu.cn.
PMID: 38394920 DOI: 10.1016/j.bioorg.2024.107215
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 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.

Keywords

Acute lung injury; Anti-inflammatory; Doublecortin-like kinase 1; Drug design.

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