학술/공연/행사

• 일시 : 2013.09.13

The met proto-oncogene product MET, the receptor for hepatocyte growth factor (HGF), has been implicated in tumorigenesis and metastatic progression. Point mutations of MET are also aberrantly activated in many types of human malignancies and their deregulated activity is correlated with tumor growth, invasion, and metastasis. MET has therefore attracted considerable attention as a potential target in anticancer therapy. Here, we report that the novel MET kinase inhibitor, AC1, inhibits various constitutively active mutant forms of MET as well as HGF-activated wild-type MET. AC1 inhibited the proliferation of cells expressing activated MET, and promoted the regression of tumors formed from such cells in a mouse xenograft model through anti-angiogenic and pro-apoptotic actions. AC1 also inhibited HGF-stimulated activation of MET signaling in the presence or absence of serum. Furthermore, in tests of 27 different MET variants, AC1 inhibited 15 of the 17 MET variants that exhibited autophosphorylation with nanomolar potency; only F1218I and M1149T variants were not inhibited by AC1. Notably, AC1 inhibited three MET variants that are resistant to the MET inhibitors SU11274, NVP-BVU972, and PHA665752. Together, these results suggest that AC1 can be used as a potent agent for the therapy of human malignancies bearing MET point mutations or expressing activated MET.