Preclinical studies and characterization of BMS-698769, a small molecule inhibitor of Met receptor tyrosine kinase

B258 The Met receptor tyrosine kinase is the exclusive high-affinity receptor for the hepatocyte growth factor (HGF) ligand. Met activation can occur by ligand binding or, as identified in multiple types of cancer, by either Met overexpression or a variety of activating mutations. Receptor activation subsequently results in a variety of pleiotropic responses that include cell motility, migration, proliferation, invasion and survival. These processes not only underlie tumor growth and metastasis, but are also critical in normal physiological processes such as wound healing and tissue regeneration. We have identified a small molecule inhibitor of Met kinase activity, BMS-698769, that inhibits both ligand stimulated and constitutive Met phosphorylation. As a result, HGF induced scattering and migration were observed to be inhibited when cells were treated with this compound. BMS-698769 also suppressed proliferation of tumor cells in which Met was constitutively active. Tumor growth inhibition in vivo was observed with the GTL-16 tumor model in which Met is amplified and activated. In addition, Met receptor phosphorylation in tumor tissue from mice treated with varying doses of BMS-698769 was inhibited in both a dose- and time-dependent manner. Because Met conditional knock-out mice exhibit significantly impaired recovery from acute liver injury, we also evaluated the potential of this compound to impair this process in adult mice using a carbon tetrachloride (CCl4) induced model of liver injury. Our results demonstrate that pharmacologically (maximum antitumor activity) relevant doses of BMS-698769 do not affect recovery from CCl4 induced liver injury. As a result, these studies suggest a low potential for tissue regeneration liabilities with BMS-698769 administration as well as the potential for targeted therapeutic intervention in cancer.