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

  • J Med Chem. 2025 Dec 25;68(24):26418-26431. doi: 10.1021/acs.jmedchem.5c02587.
Wanjing Zeng  1 ,  Xiaoyuan Hua  1 ,  Zhengyang Wang  1 ,  Kaiyin Li  1 ,  Ying Yin  1 ,  Xu-Wen Li  2  3 ,  Suzhen Dong  1 ,  Mingliang Ma  1  4
Affiliations
  • 1. Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China.
  • 2. Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, China.
  • 3. State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 4. Key Laboratory of Brain Functional Genomics-Ministry of Education, School of Life Science, East China Normal University, Shanghai 200062, China.
PMID: 41392865 DOI: 10.1021/acs.jmedchem.5c02587
Abstract

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.

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