Discovery of 6l with a New Skeleton of 6-Oxo- N-(4-(Quinolin-4-yloxy)phenyl)-1,6-dihydropyridine-3-carboxamide as a Dual-Action Inhibitor against JNK2 and the MKK7-JNK2 Protein-Protein Interaction for Acute Lung Injury

  • J Med Chem. 2026 Mar 12;69(5):5648-5676. doi: 10.1021/acs.jmedchem.5c02860.
Qi Chen  1  2 ,  Ke Dong  1  2 ,  Yaping Zhan  1 ,  Nan Huang  1  2 ,  Pan Chen  1  2 ,  Miao Jiang  2  3  4 ,  Luxiao Zhu  1  2 ,  Kaixin Zhang  2 ,  Yuehua Lv  2 ,  Yu Zou  1  2 ,  Zhichao Chen  1  2 ,  Mi Guo  1  2 ,  Chenhui Sun  2 ,  Young-Chang Cho  5 ,  Ruifeng Zeng  3  4 ,  Di Wu  1 ,  Guang Liang  1  2  6 ,  Qidong Tang  1  2
Affiliations
  • 1. Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
  • 2. Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou 325001, China.
  • 3. Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325035, China.
  • 4. Key Laboratory of Anesthesiology of Zhejiang Province, Wenzhou Medical University, Wenzhou 325035, China.
  • 5. College of Pharmacy, Chonnam National University, Gwangju 61186, South Korea.
  • 6. School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou 310053, China.
PMID: 41729167 DOI: 10.1021/acs.jmedchem.5c02860
Abstract

The development of anti-inflammatory drugs is a research focus. Acute lung injury (ALI) is a life-threatening inflammatory syndrome that currently lacks effective pharmacotherapies. Here, we report a potential therapy for ALI by targeting c-Jun N-terminal kinase 2 (JNK2), a key regulator of MAPK pathway-driven inflammatory responses. Through structure-based virtual screening and systematic structural optimization, we identified compound 6l, which potently inhibited the secretion of IL-6 in THP-1 (IC50 = 0.14 μM) and TNF-α in J774A cells (IC50 = 0.55 μM). Mechanistic studies revealed that 6l functioned through the dual inhibition of JNK2 kinase activity and the protein-protein interaction between MKK7 and JNK2, thus inhibiting the phosphorylation of c-Jun and thereby attenuating the LPS-induced inflammatory cytokine overexpression. Furthermore, 6l showed potent therapeutic effects on both LPS- and CLP-induced ALI in mice and exhibited favorable pharmacokinetics and safety profiles, establishing 6l as a promising candidate for ALI treatment.

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