Abstract
2577
The Met receptor tyrosine kinase (RTK) is the only high-affinity receptor for the hepatocyte growth factor (HGF). Met kinase activation can be achieved via HGF stimulation, Met overexpression, or a variety of activating mutations. Met activation subsequently results in pleiotropic responses that, in a cell-context dependent manner, may include cell proliferation, motility, migration, invasion, survival and angiogenesis. While these effects are important for developmental processes, when dysregulated, Met has been shown to promote tumor growth, survival and metastasis. We have identified a series of novel, potent and selective small molecule inhibitors of Met kinase activity exemplified by INCB028060. INCB028060 exhibits pM potency against Met kinase in vitro. The compound is highly specific for Met kinase with > 10,000-fold selectivity over a panel of > 50 human kinases. Using human cancer cell lines derived from tumor types where Met is frequently overexpressed, we find that INCB028060 possesses nM or sub-nM potency in blocking Met phosphorylation as well as phosphorylation of downstream effectors such as ERK, AKT, STAT3, GAB-1 and FAK. As a result, INCB028060 has demonstrated potent inhibition of Met-dependent cell migration, proliferation, and effective induction of apoptosis in tumor cells, while the compound does not inhibit the growth of tumor cells (e.g. SNU-1 gastric cancer) that do not overexpress Met. While INCB028060 does not inhibit EGFR1, EGFR3 and IGF1R directly, treatment with INCB028060 causes a dramatic reduction in phosphorylated EGFR1, EGFR3 and IGF1R in the human Met-dependent SNU5 gastric cancer and H1993 lung cancer cell lines. The data indicate that in cancer cells where the met gene is amplified, the activated Met kinase may have pleiotropic effects on multiple RTK signaling pathways and therefore could play an important role in driving tumor cell growth and survival. INCB028060 has favorable in vitro ADME characteristics and excellent in vivo PK properties. Using Met/HGF-driven xenograft mouse tumor models, we find that oral dosing of INCB028060 results in dose-dependent inhibition of tumor growth and the compound is well tolerated in mice at doses that achieve complete inhibition of tumor growth. Together, the data suggest that INCB028060 is a potent, selective and orally available Met kinase inhibitor that may have therapeutic potential.
99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA