Abstact

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease with a rapidly rising global incidence. Despite its growing prevalence, effective therapeutic options for IPF remain limited. Phosphodiesterase 4 (PDE4) inhibitors have recently emerged as promising anti-fibrotic candidates. In this study, the natural product kaempferol was identified as a weak PDE4 inhibitor with half maximal inhibitory concentration (IC(50)) of 22 muM and structure-based optimization by targeting M-pocket was performed, yielding a lead compound LH17 with dramatically improved potency (IC(50) of 73 nM). Crystallographic analysis revealed that this kaempferol-derived compound LH17 displayed distinct interactions with PDE4 M-pocket. Notably, lead LH17 demonstrated remarkable anti-fibrotic efficacy in both in vitro and in vivo models, underscoring its potential as a novel therapeutic agent for IPF treatment. This study also could establish a rational strategy for optimizing weakly bioactive natural PDE4 inhibitors into potent therapeutics.