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R. Li



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    P3.05 - Poster Session 3 - Preclinical Models of Therapeutics/Imaging (ID 159)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.05-006 - Inhibition of Tumor Cell Growth, Migration by SIM-89, a Novel Inhibitor of c-Met Tyrosine Kinase (ID 1112)

      09:30 - 09:30  |  Author(s): R. Li

      • Abstract

      Background
      It has been found that HGF-dependent c-Met（HGFR） autocrine is activated in a wide variety of human primary and second malignancies. On the other hand, the metastatic growth potential of tumors can be activated through paracrine mechanism. c-Met dysregulation leads to lung cancer development through overexpression and mutation.

      Methods
      70 kinase enzymogram screening was proceeded by Z-lyte technique. MOA analysis was completed on the inhibited kinases. Cell vitality was determined at 24h, 48h, 72h after treatment through CCK8 method. Transwell system was used to observe the inhibition of cell migration. Difference of special gene expression was evaluated by Real-time PCR. Westernblot assay was used to compare the expression difference of c-MET and p-MET. HGF level in culture medium is determined by ELISA.

      Results
      SIM-89 can inhibit 3 kinases including c-Met（IC50=297nM）, AMPK, TRKA (IC50=150.2nM). SIM-89 has an ATP competive inhibition on c-Met. By Real-time PCR, SIM-89 has been found to inhibit STAT1, JAK1, c-Met gene expression in H460 cell. P-Met expression of A549, H441, H1299 and B16F10 cell can be inhibited by SIM-89. HGF level of supernatant in culture is significantly lower than control group. Vitality of NSCLC cell lines is inhibited dependent on time and concentration by SIM-89. Induced by HGF, migration of H460, H1299 cell is inhibited.

      Conclusion
      SIM-89 has significant inhibitive effect on c-Met, TRKA kinases. It also can inhibit proliferation, migration and HGF autocrine of NSCLC cell significantly. Further study in vivo should be carried to explore the pharmacokinetics of SIM-89.