1. Design, synthesis and biological evaluation of 4-bromo-N-(3,5-dimethoxyphenyl)benzamide derivatives as novel FGFR1 inhibitors for treatment of non-small cell lung cancer
- Author
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Lu Luo, Pan Suwei, Xuebao Wang, Faqing Ye, Zhiguo Liu, Xie Zixin, Chen Bo, Guoliang Shen, Donghua Cheng, Yuan Zhang, and Yaqian Pan
- Subjects
0301 basic medicine ,MAPK/ERK pathway ,Stereochemistry ,Antineoplastic Agents ,Apoptosis ,NSCLC ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Carcinoma, Non-Small-Cell Lung ,Cell Line, Tumor ,inhibitors ,Drug Discovery ,medicine ,Humans ,Receptor, Fibroblast Growth Factor, Type 1 ,Benzamide ,Lung cancer ,Protein Kinase Inhibitors ,Cell Proliferation ,Pharmacology ,Dose-Response Relationship, Drug ,Molecular Structure ,Fibroblast growth factor receptor 1 ,lcsh:RM1-950 ,Cell Cycle Checkpoints ,molecular docking ,General Medicine ,Protein-Tyrosine Kinases ,Cell cycle ,medicine.disease ,Molecular Docking Simulation ,FGFR1 ,lcsh:Therapeutics. Pharmacology ,030104 developmental biology ,chemistry ,Cell culture ,Drug Design ,030220 oncology & carcinogenesis ,Benzamides ,Phosphorylation ,Benzamide derivatives ,Drug Screening Assays, Antitumor ,Research Paper - Abstract
A series of 4-bromo-N-(3,5-dimethoxyphenyl)benzamide derivatives were designed and synthesised as novel fibroblast growth factor receptor-1 (FGFR1) inhibitors. We found that one of the most promising compounds, C9, inhibited five non-small cell lung cancer (NSCLC) cell lines with FGFR1 amplification, including NCI-H520, NCI-H1581, NCI-H226, NCI-H460 and NCI-H1703. Moreover, the IC50 values for the compound C9 were 1.36 ± 0.27 µM, 1.25 ± 0. 23 µM, 2.31 ± 0.41 µM, 2.14 ± 0.36 µM and 1.85 ± 0.32 µM, respectively. The compound C9 arrested the cell cycle at the G2 phase in NSCLC cell lines. The compound C9 also induced cellular apoptosis and inhibited the phosphorylation of FGFR1, PLCγ1 and ERK in a dose-dependent manner. In addition, molecular docking experiments showed that compound C9 binds to FGFR1 to form six hydrogen bonds. Taken together, our data suggested that the compound C9 represented a promising lead compound-targeting FGFR1. more...
- Published
- 2019
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