c-Jun N-Terminal Kinase 3 as a Pathogenic Driver of Renal Fibrosis: Imidazo[2,1-b]thiazole-Based JNK3 Inhibitors...

Chronic kidney disease (CKD) remains an incurable global health burden, with noncanonical transforming growth factor-β (TGF-β) signaling driving fibrosis and renal dysfunction. Although c-Jun N-terminal kinase 3 (JNK3) has traditionally been regarded as a neuronal isoform, we recently uncovered its unexpected role in kidney fibrosis using JMH021, the first selective probe in this context. Building on that work, we now report an optimized imidazo[2,1-b]thiazole chemotype exemplified by 14bg, which achieved subnanomolar JNK3 potency (IC₅₀ = 0.26 nM), >400-fold selectivity over JNK1, and negligible off-target activity in kinome profiling. In human podocytes, 14bg suppressed TGF-β1-induced c-Jun phosphorylation, reduced profibrotic markers, and restored E-cadherin, an epithelial protein, without cytotoxicity. In an Adriamycin-induced nephropathy model, 14bg alleviated albuminuria, glomerulosclerosis, and podocyte foot process effacement at low doses, with superior efficacy to JMH021 and no systemic toxicity. These results provide pharmacological validation of JNK3 in CKD and establish 14bg as a promising antifibrotic lead.