title: NPS-1034, a novel MET inhibitor, inhibits the activated MET receptor and its constitutively active mutants.
abstract: 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.
authors.affiliation: Institute for Innovative Cancer Research, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 138-736, Seoul, Republic of Korea.
authors.forename: Jae-Sik
authors.initials: JS
authors.lastname: Shin
authors.forename: Seung-Woo
authors.initials: SW
authors.lastname: Hong
authors.forename: Jai-Hee
authors.initials: JH
authors.lastname: Moon
authors.forename: Jin-Sun
authors.initials: JS
authors.lastname: Kim
authors.forename: Kyung-Ah
authors.initials: KA
authors.lastname: Jung
authors.forename: Seung-Mi
authors.initials: SM
authors.lastname: Kim
authors.forename: Dae-Hee
authors.initials: DH
authors.lastname: Lee
authors.forename: InKi
authors.initials: I
authors.lastname: Kim
authors.forename: Seon-Joo
authors.initials: SJ
authors.lastname: Yoon
authors.forename: Chang-Gyu
authors.initials: CG
authors.lastname: Lee
authors.forename: Eun-Kyoung
authors.initials: EK
authors.lastname: Choi
authors.forename: Joo-Young
authors.initials: JY
authors.lastname: Lee
authors.forename: Kyu-Pyo
authors.initials: KP
authors.lastname: Kim
authors.forename: Yong Sang
authors.initials: YS
authors.lastname: Hong
authors.forename: Jae-Lyun
authors.initials: JL
authors.lastname: Lee
authors.forename: Bongcheol
authors.initials: B
authors.lastname: Kim
authors.forename: Eun Kyung
authors.initials: EK
authors.lastname: Choi
authors.forename: Jung Shin
authors.initials: JS
authors.lastname: Lee
authors.forename: Dong-Hoon
authors.initials: DH
authors.lastname: Jin
authors.forename: Tae Won
authors.initials: TW
authors.lastname: Kim
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D006574:Heterocyclic Compounds, 2-Ring / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D008817:Mice, Mutant Strains; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000090063:Proto-Oncogene Mas; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D006574:Heterocyclic Compounds, 2-Ring; C000715470:MAS1 protein, human; C000588589:NPS-1034; D047428:Protein Kinase Inhibitors; D000090063:Proto-Oncogene Mas; D011720:Pyrazoles; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met