Study On The Activity Of A Small Molecule Compound Specifically Inhibiting C-Met And Trk

Objective: Hepatocellular carcinoma(HCC)is a primary malignant tumor disease derived from liver cells.It has high morbidity and mortality,complicated pathogenesis and many attracting factors.Traditional treatment methods have problems such as poor prognosis,high recurrence rate,and short survival time.It is a serious threat to the healthy life of human beings,so there is an urgent need to develop a new strategy for the treatment of hepatocellular carcinoma.Tumor molecular targeted therapy is an advanced anti-tumor strategy in clinical practice.The drug acts on key molecules and inhibits tumor cell survival and growth,thereby achieving the purpose of clinical treatment.Receptor tyrosine kinases(RTKs)are classic targets for the treatment of tumors,significant advances have been made in the development of small molecule inhibitors(SMIs)and monoclonal antibodies(mAbs)for these targets.Studies have shown that c-Met and Trk kinase are closely related to the occurrence and development of various cancers including hepatocellular carcinoma.Targeting inhibition of these two kinase activities may be an effective method for treating hepatocellular carcinoma.The aim of this study was to determine whether there is a synergistic relationship between HGF/c-Met signaling pathway and Trk signaling pathway.The anti-tumor activity of a small molecule compound L029 specifically targeting c-Met and Trk on hepatocellular carcinoma and the characteristics of metabolism and tissue distribution in vivo will be further studied in this experiment,which may provide a new therapeutic strategy for hepatocellular carcinoma.Methods: The relationship between HGF/c-Met and Trk signaling pathway was studied by cell experiments.Western blot was used to detect the response of each signal pathway to the corresponding cytokine stimulation.Selective inhibitors or low doses of HGF and BDNF treated HepG2 cells.The difference of protein phosphorylation levels between the experimental group and the control group was compared.To evaluate of antitumor activity of L029 inclusion compound by nude mouse hepatocellular carcinoma orthotopic transplantation model.An orthotopic transplantation model of hepatocellular carcinoma which can be used for in vivo fluorescence imaging was established by using luciferase labeled hepatocarcinoma cells.The metabolism and tissue distribution of the compound were investigated by single tail vein injection of L029.Results: There is a synergistic relationship between c-Met and Trk.L029 inclusion compounds can inhibit the growth of HepG2 cells and intrahepatic metastasis of MHCC97 H cells in nude mice,and improve the survival rate of nude mice.L029 is rapidly metabolized in the body,mainly distributed in the liver and kidney,and can not pass the blood-brain barrier and the blood-testis barrier.The luciferase labeled hepatocellular carcinoma orthotopic transplantation model was successfully established.It lays the foundation for the subsequent dynamic evaluation of L029 inhibition of hepatocellular carcinoma activity.Conclusion: This study revealed a clear synergistic relationship between HGF/c-Met and Trk signaling pathway.As a c-Met and Trk kinase specific inhibitor,L029 have good anti-tumor activity against hepatocellular carcinoma.It metabolizes rapidly in the body,but is concentrated in the liver.This suggests that combined targeting of c-Met and Trk kinase may be an effective way to treat hepatocellular carcinoma.In addition,the successful establishment of a luciferase labeled hepatocellular carcinoma orthotopic transplantation model lays the foundation for the evaluation of L029 anti-hepatocarcinoma activity.