Potential Antitumor Activity of SIM-89 in Non-Small Cell Lung Cancer Cells

Yonsei Med J. 2017 May;58(3):581-591. doi: 10.3349/ymj.2017.58.3.581.


Purpose: c-Met and its ligand, hepatocyte growth factor (HGF), play a critical role in oncogenesis and metastatic progression. The aim of this study was to identify inhibited enzymogram and to test the antitumor activity of SIM-89 (a c-Met receptor tyrosine kinase inhibitor) in non-small cell lung cancer.

Materials and methods: Z'-LYTE kinase assay was employed to screen the kinase enzymogram, and mechanism of action (MOA) analysis was used to identify the inhibited kinases. Cell proliferation was then analyzed by CCK8 assay, and cell migration was determined by transwell assay. The gene expression and the phosphorylation of c-Met were examined by realtime-PCR and western blotting, respectively. Finally, the secretion of HGF was detected by ELISA assay.

Results: c-Met, activated protein kinase (AMPK), and tyrosine kinase A (TRKA) were inhibited by SIM-89 with the IC₅₀ values of 297 nmol/L, 1.31 μmol/L, and 150.2 nmol/L, respectively. SIM-89 exerted adenosine triphosphate (ATP) competitive inhibition on c-Met. Moreover, the expressions of STAT1, JAK1, and c-Met in H460 cells were decreased by SIM-89 treatment, and c-Met phosphorylation was suppressed in A549, H441, H1299, and B16F10 cells by the treatment. In addition, SIM-89 treatment significantly decreased the level of HGF, which accounted for the activation of c-Met receptor tyrosine kinase. Finally, we showed cell proliferation inhibition and cell migration suppression in H460 and H1299 cells after SIM-89 treatment.

Conclusion: In conclusion, SIM-89 inhibits tumor cell proliferation, migration and HGF autocrine, suggesting it's potential antitumor activity.

Keywords: antitumor; c-Met; cell migration; cell proliferation; lung cancer.

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Blotting, Western
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / enzymology
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Line, Tumor*
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects*
  • Enzyme-Linked Immunosorbent Assay
  • Hepatocyte Growth Factor / metabolism
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / enzymology
  • Lung Neoplasms / pathology
  • Phosphorylation
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins c-met / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-met / genetics*
  • Proto-Oncogene Proteins c-met / metabolism
  • Signal Transduction / drug effects
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • HGF protein, human
  • Protein Kinase Inhibitors
  • Hepatocyte Growth Factor
  • MET protein, human
  • Proto-Oncogene Proteins c-met