title: Novel c-Met inhibitor suppresses the growth of c-Met-addicted gastric cancer cells.
abstract: BACKGROUND
  c-Met signaling has been implicated in oncogenesis especially in cells with c-met gene amplification. Since 20 % of gastric cancer patients show high level of c-Met expression, c-Met has been identified as a good candidate for targeted therapy in gastric cancer. Herein, we report our newly synthesized c-Met inhibitor by showing its efficacy both in vitro and in vivo.
  
  
  METHODS
  Compounds with both triazolopyrazine and pyridoxazine scaffolds were synthesized and tested using HTRF c-Met kinase assay. We performed cytotoxic assay, cellular phosphorylation assay, and cell cycle assay to investigate the cellular inhibitory mechanism of our compounds. We also conducted mouse xenograft assay to see efficacy in vivo.
  
  
  RESULTS
  KRC-00509 and KRC-00715 were selected as excellent c-Met inhibitors through biochemical assay, and exhibited to be exclusively selective to c-Met by kinase panel assay. Cytotoxic assays using 18 gastric cancer cell lines showed our c-Met inhibitors suppressed specifically the growth of c-Met overexpressed cell lines, not that of c-Met low expressed cell lines, by inducing G1/S arrest. In c-met amplified cell lines, c-Met inhibitors reduced the downstream signals including Akt and Erk as well as c-Met activity. In vivo Hs746T xenograft assay showed KRC-00715 reduced the tumor size significantly.
  
  
  CONCLUSIONS
  Our in vitro and in vivo data suggest KRC-00715 is a potent and highly selective c-Met inhibitor which may have therapeutic potential in gastric tumor with c-Met overexpression.
authors.affiliation: Bio-Organic Science Division, Korea Research Institute of Chemical Technology, PO Box 107, Daejeon, 305-600, Republic of Korea.|Medicinal Chemistry and Pharmacology, Korea University of Science and Technology, Daejeon, 305-350, Republic of Korea.
authors.forename: Chi Hoon
authors.initials: CH
authors.lastname: Park
authors.affiliation: Bio-Organic Science Division, Korea Research Institute of Chemical Technology, PO Box 107, Daejeon, 305-600, Republic of Korea.|Medicinal Chemistry and Pharmacology, Korea University of Science and Technology, Daejeon, 305-350, Republic of Korea.
authors.forename: Sung Yun
authors.initials: SY
authors.lastname: Cho
authors.affiliation: Bio-Organic Science Division, Korea Research Institute of Chemical Technology, PO Box 107, Daejeon, 305-600, Republic of Korea.
authors.forename: Jae Du
authors.initials: JD
authors.lastname: Ha
authors.affiliation: Bio-Organic Science Division, Korea Research Institute of Chemical Technology, PO Box 107, Daejeon, 305-600, Republic of Korea.|Medicinal Chemistry and Pharmacology, Korea University of Science and Technology, Daejeon, 305-350, Republic of Korea.
authors.forename: Heejung
authors.initials: H
authors.lastname: Jung
authors.affiliation: Bio-Organic Science Division, Korea Research Institute of Chemical Technology, PO Box 107, Daejeon, 305-600, Republic of Korea.
authors.forename: Hyung Rae
authors.initials: HR
authors.lastname: Kim
authors.affiliation: Bio-Organic Science Division, Korea Research Institute of Chemical Technology, PO Box 107, Daejeon, 305-600, Republic of Korea.
authors.forename: Chong Ock
authors.initials: CO
authors.lastname: Lee
authors.affiliation: Bio-Organic Science Division, Korea Research Institute of Chemical Technology, PO Box 107, Daejeon, 305-600, Republic of Korea.
authors.forename: In-Young
authors.initials: IY
authors.lastname: Jang
authors.affiliation: Bio-Organic Science Division, Korea Research Institute of Chemical Technology, PO Box 107, Daejeon, 305-600, Republic of Korea.
authors.forename: Chong Hak
authors.initials: CH
authors.lastname: Chae
authors.affiliation: Bio-Organic Science Division, Korea Research Institute of Chemical Technology, PO Box 107, Daejeon, 305-600, Republic of Korea.
authors.forename: Heung Kyoung
authors.initials: HK
authors.lastname: Lee
authors.affiliation: Bio-Organic Science Division, Korea Research Institute of Chemical Technology, PO Box 107, Daejeon, 305-600, Republic of Korea. suchoi@krict.re.kr.
authors.forename: Sang Un
authors.initials: SU
authors.lastname: Choi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000138:chemical synthesis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000138:chemical synthesis; D019859:Proto-Oncogene Proteins c-met / Q000096:biosynthesis* / Q000235:genetics; D011719:Pyrazines / Q000008:administration & dosage* / Q000138:chemical synthesis; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D014230:Triazoles / Q000008:administration & dosage* / Q000138:chemical synthesis; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C000611314:KRC-00509; C000611313:KRC-00715; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D014230:Triazoles; D019859:Proto-Oncogene Proteins c-met