c‑Jun N‑Terminal Kinase 3 as a Pathogenic Driver of Renal Fibrosis: Imidazo[2,1‑b]thiazole-Based JNK3 Inhibitors Restore Podocyte Function in TGF-β-Mediated Glomerulosclerosis

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.