A novel kinase inhibitor, INCB28060, blocks c-MET-dependent signaling, neoplastic activities, and cross-talk with EGFR and HER-3.
The c-MET receptor tyrosine kinase plays important roles in the formation, progression, and dissemination of human cancer and presents an attractive therapeutic target. This study describes the preclinical characterization of INCB28060, a novel inhibitor of c-MET kinase.Studies were conducted using a series of in vitro and in vivo biochemical and ... biological experiments.INCB28060 exhibits picomolar enzymatic potency and is highly specific for c-MET with more than 10,000-fold selectivity over a large panel of human kinases. This inhibitor potently blocks c-MET phosphorylation and activation of its key downstream effectors in c-MET-dependent tumor cell lines. As a result, INCB28060 potently inhibits c-MET-dependent tumor cell proliferation and migration and effectively induces apoptosis in vitro. Oral dosing of INCB28060 results in time- and dose-dependent inhibition of c-MET phosphorylation and tumor growth in c-MET-driven mouse tumor models, and the inhibitor is well tolerated at doses that achieve complete tumor inhibition. In a further exploration of potential interactions between c-MET and other signaling pathways, we found that activated c-MET positively regulates the activity of epidermal growth factor receptors (EGFR) and HER-3, as well as expression of their ligands. These effects are reversed with INCB28060 treatment. Finally, we confirmed that circulating hepatocyte growth factor levels are significantly elevated in patients with various cancers.Activated c-MET has pleiotropic effects on multiple cancer-promoting signaling pathways and may play a critical role in driving tumor cell growth and survival. INCB28060 is a potent and selective c-MET kinase inhibitor that may have therapeutic potential in cancer treatment.
Mesh Terms:
Animals, Antineoplastic Agents, Benzamides, Bridged Bicyclo Compounds, Heterocyclic, Cell Line, Tumor, Dose-Response Relationship, Drug, Enzyme Activation, Female, Glioblastoma, Humans, Mice, Mice, Nude, Neoplasms, Experimental, Phosphorylation, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-met, Receptor Cross-Talk, Receptor, Epidermal Growth Factor, Receptor, ErbB-3, Signal Transduction, Xenograft Model Antitumor Assays
Animals, Antineoplastic Agents, Benzamides, Bridged Bicyclo Compounds, Heterocyclic, Cell Line, Tumor, Dose-Response Relationship, Drug, Enzyme Activation, Female, Glioblastoma, Humans, Mice, Mice, Nude, Neoplasms, Experimental, Phosphorylation, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-met, Receptor Cross-Talk, Receptor, Epidermal Growth Factor, Receptor, ErbB-3, Signal Transduction, Xenograft Model Antitumor Assays
Clin. Cancer Res.
Date: Nov. 15, 2011
PubMed ID: 21918175
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