W014 Is A Potent Inhibitor Of Hepatocyte Growth Factor Receptor (c-Met) And Blocks HGF-induced Biological Effection

Hepatocyte growth factor (HGF), also known as scatter factor (SF), is a multifunctional cell factor which predominantly expressed in mesenchymal origin. c-Met tyrosine kinase is the only known high-affinity receptor for HGF. HGF/c-Met signal pathway is abnormally activated in mostly solid tumors, and it concerned with acromegatic prognosis. Preliminary studies showed that inhibiting of the HGF/c-Met signal pathway will retrieve the growth, invasion and metastasis of tumor cells. HGF/c-Met has been represented as a world-wide recognized target for cancer therapy.In early study, according to the biological characteristics of HGF/c-Met, we devised a platform to screen new drugs for cancer. We found one compound named W014, which could inhibit the activation of HGF/c-Met signal pathway. This thesis systemic studied the characteristics of W014 inhibiting HGF/c-Met signal pathway, discovered W014 could inhibit c-Met phosphorylation in the low micromole range, also block c-Met mediated signal pathway. W014 could inhibit HGF/c-Met mediated diverse biologic effect, including cell invasion and proliferation induced by HGF, and continuing activated mutant(TPR-MET)resulted cell malignant transformation.W014 had few effect on single pathway induced by EGF and VEGF, indicating that W014 had determinate specificity in inhibiting c-Met activity. These results indicated W014 could be a lead compound for HGF/c-Met inhibitor. Furthermore, in the substruction of W014 we synthesisd and appraised 200 compound, detected W014 had the most apparent effect.