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

Journal of Enzyme Inhibition and Medicinal Chemistry

Yaqian Pan¹  Yuan Zhang¹  Donghua Cheng¹  Bo Chen¹  Suwei Pan¹  Zixin Xie¹  Lu Luo¹  Xuebao Wang¹  Guoliang Shen¹  Zhiguo Liu¹  Faqing Ye¹ 

[1]School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, Chin

关键词: Benzamide derivatives;    FGFR1;    inhibitors;    molecular docking;    NSCLC;   

DOI  :  10.1080/14756366.2018.1460824

来源: publisher

【 摘 要 】

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.

【 授权许可】

CC BY