201. Identification of imidazo[4,5-c]pyridin-2-one derivatives as novel Src family kinase inhibitors against glioblastoma
- Author
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Lishun Zhang, Zichao Yang, Ying Jiang, Jiajie Zhang, Xingmei Zhang, Shanhe Wan, Huiting Sang, Chunhui Huang, Mingfeng Zhou, Tingting Zhang, Chuan Huang, and Xiaoyun Wu
- Subjects
Models, Molecular ,kinase inhibitor ,Antineoplastic Agents ,src family kinase ,RM1-950 ,Quinolones ,molecular simulation ,Structure-Activity Relationship ,FYN ,Cell Line, Tumor ,Drug Discovery ,Humans ,Src family kinase ,Binding site ,U87 ,Protein Kinase Inhibitors ,ADME ,Cell Proliferation ,Pharmacology ,Dose-Response Relationship, Drug ,Molecular Structure ,Chemistry ,Kinase ,Brain Neoplasms ,Imidazoles ,glioblastoma ,General Medicine ,nervous system diseases ,src-Family Kinases ,imidazo[4,5-c]pyridin-2-one ,Cell culture ,Cancer research ,Therapeutics. Pharmacology ,Drug Screening Assays, Antitumor ,Proto-oncogene tyrosine-protein kinase Src ,Research Article ,Research Paper - Abstract
Glioblastoma multiforme (GBM) is the most common and malignant primary brain tumour in the central nervous system (CNS). As the ideal targets for GBM treatment, Src family kinases (SFKs) have attracted much attention. Herein, a new series of imidazo[4,5-c]pyridin-2-one derivatives were designed and synthesised as SFK inhibitors. Compounds 1d, 1e, 1q, 1s exhibited potential Src and Fyn kinase inhibition in the submicromolar range, of which were next tested for their antiproliferative potency on four GBM cell lines. Compound 1s showed effective activity against U87, U251, T98G, and U87-EGFRvIII GBM cell lines, comparable to that of lead compound PP2. Molecular dynamics (MDs) simulation revealed the possible binding patterns of the most active compound 1s in ATP binding site of SFKs. ADME prediction suggested that 1s accord with the criteria of CNS drugs. These results led us to identify a novel SFK inhibitor as candidate for GBM treatment., Graphical Abstract
- Published
- 2021