Journal
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
Volume 33, Issue 1, Pages 905-919Publisher
TAYLOR & FRANCIS LTD
DOI: 10.1080/14756366.2018.1460824
Keywords
Benzamide derivatives; FGFR1; inhibitors; molecular docking; NSCLC
Funding
- National Natural Science Foundation of China [81373262, 81773579]
- Science Foundation of Zhejiang Province [LY16B020010, LY17B020008]
- Opening Project of Zhejiang Provincial Top Key Discipline of Pharmaceutical Sciences [201710, 201715]
- Science and Technology Project of Wenzhou [Y20150110]
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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 mu M, 1.25 +/- 0.23 mu M, 2.31 +/- 0.41 mu M, 2.14 +/- 0.36 mu M and 1.85 +/- 0.32 mu M, 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, PLC gamma 1 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.
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