中国科学院机构知识库网格
Chinese Academy of Sciences Institutional Repositories Grid
首页 机构 成果 学者
  
  1. CAS IR Grid
  2. 上海药物研究所
  3. 中国科学院上海药物研究所
Discovery of Imidazo[1,2-b]pyridazine Derivatives as Potent PI3K/mTOR Dual Inhibitors for the Treatment of Pulmonary Fibrosis

文献类型：期刊论文

作者Zeng, Wanjing3; Hua, Xiaoyuan3; Wang, Zhengyang3; Li, Kaiyin3; Yin, Ying3; Li, Xu-wen1,2; Dong, Suzhen3; Ma, Mingliang3,4
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2025-12-25
卷号68期号:24页码:26418-26431
ISSN号0022-2623
DOI10.1021/acs.jmedchem.5c02587
通讯作者Dong, Suzhen(szdong@brain.ecnu.edu.cn) ; Ma, Mingliang(mlma@brain.ecnu.edu.cn)
英文摘要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% PI3K alpha, 42.99% mTOR at 1 nM) and nanomolar antiproliferative effects in pulmonary fibroblasts (IC50 = 0.380 and 0.090 mu M). 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.
WOS关键词PHOSPHATIDYLINOSITOL 3-KINASE ; GROWTH ; PIRFENIDONE ; TISSUE
资助项目Fundamental Research Funds for the Central Universities[NA] ; Shandong Laboratory Program[NA]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001639290900001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/322381]  
专题中国科学院上海药物研究所
通讯作者Dong, Suzhen; Ma, Mingliang
作者单位1.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Chem Biol, Shanghai 201203, Peoples R China
3.East China Normal Univ, Shanghai Engn Res Ctr Mol Therapeut & New Drug Dev, Sch Chem & Mol Engn, Shanghai 200062, Peoples R China
4.East China Normal Univ, Sch Life Sci, Key Lab Brain Funct Genom, Minist Educ, Shanghai 200062, Peoples R China
推荐引用方式
GB/T 7714		 Zeng, Wanjing,Hua, Xiaoyuan,Wang, Zhengyang,et al. Discovery of Imidazo[1,2-b]pyridazine Derivatives as Potent PI3K/mTOR Dual Inhibitors for the Treatment of Pulmonary Fibrosis[J]. JOURNAL OF MEDICINAL CHEMISTRY,2025,68(24):26418-26431.
APA Zeng, Wanjing.,Hua, Xiaoyuan.,Wang, Zhengyang.,Li, Kaiyin.,Yin, Ying.,...&Ma, Mingliang.(2025).Discovery of Imidazo[1,2-b]pyridazine Derivatives as Potent PI3K/mTOR Dual Inhibitors for the Treatment of Pulmonary Fibrosis.JOURNAL OF MEDICINAL CHEMISTRY,68(24),26418-26431.
MLA Zeng, Wanjing,et al."Discovery of Imidazo[1,2-b]pyridazine Derivatives as Potent PI3K/mTOR Dual Inhibitors for the Treatment of Pulmonary Fibrosis".JOURNAL OF MEDICINAL CHEMISTRY 68.24(2025):26418-26431.

入库方式： OAI收割

来源：上海药物研究所

浏览0
下载0
收藏0
其他版本

除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。