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

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.PMID:38394920 | DOI:10.1016/j.bioorg.2024.107215

Source: Bioorganic Chemistry - February 23, 2024 Category: Chemistry Authors: Binhao Cai Ying Xu Ruixiang Luo Kongqin Lu Yuhan Wang Lei Zheng Yawen Zhang Lina Yin Linglan Tu Wu Luo Lulu Zheng Fengzhi Zhang Xinting Lv Qidong Tang Guang Liang Lingfeng Chen Source Type: research