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

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.