Design, synthesis, and activity study of heterocyclic derivatives as JAK inhibitors

The Janus kinase (JAK) family plays a central role in regulating inflammation and fibrosis through the JAK/STAT signaling pathway, making it an attractive therapeutic target for immune-mediated diseases. In the present study, structural modifications of the quinazoline core were systematically explored to identify potent JAK inhibitors. A CXCL10-based screening strategy identified compound 22a as a promising lead, exhibiting strong inhibitory activity in HaCaT cells with an IC₅₀ value of 308 nM. Subsequent kinase assays demonstrated that compound 22a exhibits higher inhibitory potency toward JAK1 (IC₅₀ = 37.86 nM) compared to JAK2 (IC₅₀ = 102.5 nM), JAK3 (IC₅₀ = 69.35 nM), and TYK2 (IC₅₀ = 2142 nM). Mechanistic studies revealed a dose-dependent suppression of STAT1 phosphorylation, confirming inhibition of the JAK1/2–STAT1 signaling pathway. In addition, molecular docking and molecular dynamics simulations were performed to elucidate and validate the binding mode of compound 22a within the JAK1 active site. Collectively, these results indicate that the developed quinazoline derivatives represent promising leads for the further development of selective JAK1 inhibitors.