title: KRC-327, a selective novel inhibitor of c-Met receptor tyrosine kinase with anticancer activity.
abstract: c-Met receptor tyrosine kinase and its ligand, hepatocyte growth factor (HGF), have been reported to be involved in tumorigenesis and metastatic progression. We synthesized a novel triazolopyridazine derivative KRC-327 which selectively targets the c-Met. When we performed receptor tyrosine kinases (RTKs) array with 42 different phosphorylated-RTKs, KRC-327 strongly inhibited expression of activated c-Met in MKN-45 cancer cells. This was confirmed by immunofluorescence staining. Also, KRC-327 decreased the expression of Gab1, Akt, signal transducer and activator of transcription 3 (STAT3) and Erk, down-stream signals of c-Met. KRC-327 strongly suppressed the growth of c-Met over-expressed cancer cells (MKN-45, SNU-638, SNU-5), while not in c-Met absent cancer cell lines (MKN-1, SNU-1). Furthermore, KRC-327 effectively induced cell cycle arrest, especially G0/G1 arrest by increasing expression of p21, p27 and decreasing that of cyclin D1. In the ligand-induced functional studies, KRC-327 inhibited proliferation of HGF-stimulated BxPC-3 cells, the migration of HGF-stimulated AGS cancer cells, and suppressed colony formation in HGF-stimulated U-87MG cells. In xenograft animal models, KRC-327 significantly not only delayed tumor growth but also suppressed phosphorylation of c-Met and its signaling cascades as well as proliferation. Taken together, these results demonstrate that KRC-327 selectively targets c-Met, resulting in inhibition of cell growth and proliferation. Therefore, we suggest that KRC-327 may be a novel drug candidate with the therapeutic potential of targeting c-Met in human cancer.
authors: Department of Biomedical Sciences, College of Medicine, Inha University, 3-ga, Sinheung-dong, Jung-gu, Incheon 400-712, Republic of Korea.
authors: Byung Hee
authors: BH
authors: Park
authors: Kyung Hee
authors: KH
authors: Jung
authors: Sun-Mi
authors: SM
authors: Yun
authors: Sang-Won
authors: SW
authors: Hong
authors: Jae Wook
authors: JW
authors: Ryu
authors: Heejung
authors: H
authors: Jung
authors: Jae Du
authors: JD
authors: Ha
authors: Jongkook
authors: J
authors: Lee
authors: Soon-Sun
authors: SS
authors: Hong
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D005455:Fluorescent Antibody Technique; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology*; D009369:Neoplasms / Q000473:pathology*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011724:Pyridazines / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C580771:5-((6-phenyl-(1,2,4)triazolo(4,3-b)pyridazin-3-yl)methyl)isoquinolin-1(2H)-one; D000970:Antineoplastic Agents; D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases