2. Academic Validation
  3. 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

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

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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