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: Byung Hee Park, Kyung Hee Jung, Sun-Mi Yun, Sang-Won Hong, Jae Wook Ryu, Heejung Jung, Jae Du Ha, Jongkook Lee, Soon-Sun Hong
• Journal: Cancer letters (Cancer Lett) Vol. 331 Issue 2 Pg. 158-66 (May 01 2013) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 23340177 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Crown Copyright © 2013. Published by Elsevier Ireland Ltd. All rights reserved.

Chemical References

• 5-((6-phenyl-(1,2,4)triazolo(4,3-b)pyridazin-3-yl)methyl)isoquinolin-1(2H)-one
• Antineoplastic Agents
• Isoquinolines
• Protein Kinase Inhibitors
• Pyridazines
• RON protein
• Receptor Protein-Tyrosine Kinases

Topics

• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor
• Drug Screening Assays, Antitumor
• Fluorescent Antibody Technique
• Humans
• Isoquinolines (pharmacology)
• Neoplasms (pathology)
• Phosphorylation
• Protein Kinase Inhibitors (pharmacology)
• Pyridazines (pharmacology)
• Receptor Protein-Tyrosine Kinases (antagonists & inhibitors, metabolism)