Discovery of Imidazo[1,2‑b]pyridazine Derivatives as Potent PI3K/mTOR Dual Inhibitors for the Treatment of Pulmonary Fibrosis

The PI3K/AKT/mTOR pathway drives fibrotic progression in idiopathic pulmonary fibrosis (IPF). Our design strategy yielded a series of novel imidazo[1,2-b]pyridazine-based dual PI3K/mTOR inhibitors. Guided by molecular docking, structural optimization introduced phenolic hydroxyl and carboxylic acid groups, enhancing binding and antifibrotic abilities. Compound 11 exhibited potent inhibition (94.9% PI3Kα, 42.99% mTOR at 1 nM) and nanomolar antiproliferative effects in pulmonary fibroblasts (IC50 = 0.380 and 0.090 μM). In a bleomycin-induced pulmonary fibrosis model, compound 11 (15 mg/kg) reduced Ashcroft scores, hydroxyproline content, and collagen deposition while restoring lung architecture. Western blot analysis confirmed the downregulation of fibrosis-related proteins. Treated mice showed steady weight recovery. Besides, toxicity test results showed no distinct liver and kidney toxicity in 11-treated mice at therapeutic doses. This work identifies a promising IPF therapeutic lead and establishes a framework for optimizing imidazo[1,2-b]pyridazine scaffolds in antifibrotic drug development.