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

J Enzyme Inhib Med Chem. 2018 Dec;33(1):905-919. doi: 10.1080/14756366.2018.1460824.

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.

Keywords: Benzamide derivatives; FGFR1; NSCLC; inhibitors; molecular docking.

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Benzamides / chemical synthesis
  • Benzamides / chemistry
  • Benzamides / pharmacology*
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Cycle Checkpoints / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Drug Screening Assays, Antitumor
  • Humans
  • Molecular Docking Simulation
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / metabolism
  • Receptor, Fibroblast Growth Factor, Type 1 / antagonists & inhibitors*
  • Receptor, Fibroblast Growth Factor, Type 1 / metabolism
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Benzamides
  • Protein Kinase Inhibitors
  • benzamide
  • FGFR1 protein, human
  • Protein-Tyrosine Kinases
  • Receptor, Fibroblast Growth Factor, Type 1

Grants and funding

The authors would like to thank the National Natural Science Foundation of China [no. 81373262, 81773579], the Science Foundation of Zhejiang Province [no. LY16B020010, LY17B020008], the Opening Project of Zhejiang Provincial Top Key Discipline of Pharmaceutical Sciences [no. 201710, 201715] and the Science and Technology Project of Wenzhou [no. Y20150110] for their financial support.