A novel inhibitor of c-Met and VEGF receptor tyrosine kinases with a broad spectrum of in vivo antitumor activities

• Published in: Molecular cancer therapeutics Vol. 12; no. 6; pp. 913 - 924
• Main Authors: Awazu, Yoshiko, Nakamura, Kazuhide, Mizutani, Akio, Kakoi, Yuichi, Iwata, Hidehisa, Yamasaki, Seiji, Miyamoto, Naoki, Imamura, Shinichi, Miki, Hiroshi, Hori, Akira
• Format: Journal Article
• Language: English
• Published: United States 01.06.2013
• Subjects: Angiogenesis Inhibitors - administration & dosage; Animals; Cell Line, Tumor; Cell Proliferation - drug effects; Endothelial Cells - drug effects; Endothelial Cells - pathology; Gene Expression Regulation, Neoplastic - drug effects; Hepatocyte Growth Factor - antagonists & inhibitors; Hepatocyte Growth Factor - genetics; Heterocyclic Compounds, 2-Ring - administration & dosage; Human Umbilical Vein Endothelial Cells - drug effects; Humans; Mice; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - pathology; Niacinamide - administration & dosage; Niacinamide - analogs & derivatives; Protein Kinase Inhibitors - administration & dosage; Proto-Oncogene Proteins c-met - antagonists & inhibitors; Proto-Oncogene Proteins c-met - genetics; Signal Transduction - drug effects; Stomach Neoplasms - blood supply; Stomach Neoplasms - drug therapy; Stomach Neoplasms - pathology; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism; Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors; Vascular Endothelial Growth Factor Receptor-2 - metabolism; Xenograft Model Antitumor Assays
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-12-1011

The c-Met receptor tyrosine kinase and its ligand, hepatocyte growth factor (HGF), are dysregulated in a wide variety of human cancers and are linked with tumorigenesis and metastatic progression. VEGF also plays a key role in tumor angiogenesis and progression by stimulating the proangiogenic signaling of endothelial cells via activation of VEGF receptor tyrosine kinases (VEGFR). Therefore, inhibiting both HGF/c-Met and VEGF/VEGFR signaling may provide a novel therapeutic approach for treating patients with a broad spectrum of tumors. Toward this goal, we generated and characterized T-1840383, a small-molecule kinase inhibitor that targets both c-Met and VEGFRs. T-1840383 inhibited HGF-induced c-Met phosphorylation and VEGF-induced VEGFR-2 phosphorylation in cancer epithelial cells and vascular endothelial cells, respectively. It also inhibited constitutively activated c-Met phosphorylation in c-met-amplified cancer cells, leading to suppression of cell proliferation. In addition, T-1840383 potently blocked VEGF-dependent proliferation and capillary tube formation of endothelial cells. Following oral administration, T-1840383 showed potent antitumor efficacy in a wide variety of human tumor xenograft mouse models, along with reduction of c-Met phosphorylation levels and microvessel density within tumor xenografts. These results suggest that the efficacy of T-1840383 is produced by direct effects on tumor cell growth and by an antiangiogenic mechanism. Furthermore, T-1840383 showed profound antitumor activity in a gastric tumor peritoneal dissemination model. Collectively, our findings indicate the therapeutic potential of targeting both c-Met and VEGFRs simultaneously with a single small-molecule inhibitor for the treatment of human cancers.