Structure Optimization of C-Jun N-terminal Kinase 1 Inhibitors for Treating Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal lung disease with an elusive etiology. Aberrant activation of c-Jun N-terminal kinase 1 (JNK1) has been implicated in its pathogenesis. Through a combination of structure-based drug design and structure-activity relationship (SAR) optimization, a series of pyrimidine-2,4-diamine scaffold derivatives have been developed as potent JNK1 inhibitors. Compound was identified with low nanomolar JNK1 inhibitory potency (IC = 2.7 nM). The introduction of a dimethylamine side chain has significantly enhanced the ability of to inhibit c-Jun phosphorylation, surpassing the clinical candidate . Molecular dynamics simulations revealed a binding free energy of -50.46 kcal/mol for . Moreover, displayed satisfactory pharmacokinetic properties, with a bioavailability of 69% in rats. Furthermore, compound exerted significant antifibrotic effects in a bleomycin-induced IPF mouse model and prevented a TGF-β-induced epithelial-to-mesenchymal transition in vitro. These findings position as a promising lead for further drug development targeting IPF.