NPS-1034, a novel MET inhibitor, inhibits the activated MET receptor and its constitutively active mutants

作者：Shin Jae Sik; Hong Seung Woo; Moon Jai Hee; Kim Jin Sun; Jung Kyung Ah; Kim Seung Mi; Lee Dae Hee; Kim InKi; Yoon Seon Joo; Lee Chang Gyu; Choi Eun Kyoung; Lee Joo Young; Kim Kyu pyo; Hong Yong Sang; Lee Jae Lyun; Kim Bongcheol; Choi Eun Kyung; Lee Jung Shin; Jin Dong Hoon^*; Kim Tae Won

来源：Investigational New Drugs, 2014, 32(3): 389-399.

DOI：10.1007/s10637-013-0039-4

• NPS-1034
• MET
• Constitutively active mutants
• Hepatocyte growth factor (HGF)

The MET proto-oncogene product, which is the receptor for hepatocyte growth factor (HGF), has been implicated in tumorigenesis and metastatic progression. Point mutations in MET lead to the aberrant activation of the receptor in many types of human malignancies, and the deregulated activity of MET has been correlated with tumor growth, invasion, and metastasis. MET has therefore attracted considerable attention as a potential target in anticancer therapy. Here, we report that a novel MET kinase inhibitor, NPS-1034, inhibits various constitutively active mutant forms of MET as well as HGF-activated wild-type MET. NPS-1034 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. NPS-1034 also inhibited HGF-stimulated activation of MET signaling in the presence or absence of serum. Furthermore, when tested on 27 different MET variants, NPS-1034 inhibited 15 of the 17 MET variants that exhibited autophosphorylation with nanomolar potency; only the F1218I and M1149T variants were not inhibited by NPS-1034. Notably, NPS-1034 inhibited three MET variants that are resistant to the MET inhibitors SU11274, NVP-BVU972, and PHA665752. Together, these results suggest that NPS-1034 can be used as a potent therapeutic agent for human malignancies bearing MET point mutations or expressing activated MET.

• 出版日期2014-6