Rheumatoid arthritis (RA) is a chronic disease, characterized mainly by inflammation of the lining, or synovium, of the joints. It can lead to long-term joint damage, resulting in chronic pain, loss of function and disability. Approximately 2.1 million people in the United States, or 1% of the population, have RA. It can affect anyone, including children, but 70% of people with RA are women. Onset usually occurs between 30 and 50 years of age. RA often goes into remission in pregnant women, although symptoms tend to increase in intensity after delivery. RA develops more often than expected the year after giving birth. While women are two to three times more likely to get RA than men, men tend to be more severely affected when afflicted. Inflammation and angiogenesis are two of the fundamental processes that underlie pathologic disorders. Tissue injury induces inflammation, and inflammation triggers angiogenesis, which in turn, initiates tissue repair and tissue growth. Persistent angiogenesis is critical both to maintaining the chronic architectural changes in the RA synovium via delivery of nutrients and inflammatory cells, and to providing an important source of cytokines and protease activity. Met and Tie2 are two receptor tyrosine kinases that have been identified as therapeutic targets against angiogenesis. Using a drug discovery engine, Angion identified the small molecule Ang797, an active kinase inhibitor that competes with ATP for the ATP-binding site of Met. Our results indicate that Ang797 significantly and selectively inhibits Met activation and inhibits downstream signaling events initiated by its ligand, hepatocyte growth factor/scatter factor (HGF/SF). Moreover, Ang797 also inhibits activity of a second RTK associated with angiogenesis, Tie-2. In vitro, Ang797 inhibits endothelial and tumor cell growth and, most relevant here, HGF/SF-induced angiogenesis. In the rat model of collagen induced arthritis (CIA), Ang797 ameliorates the disease course and reduces tissue damage. Our preliminary data show that Ang797 and its analogs act as specific inhibitors of Met and Tie2 kinase cascade pathways, down-regulate angiogenesis and neo-vascularization, ameliorate the course of the disease and promote functional recovery in CIA. At Angion, we are using the Met crystal structure, molecular modeling, and medicinal chemistry approach to increase the potency of Ang797. The goal of this application is to evaluate the anti-RA effects of Ang797 and its analogs on anti-angiogenesis activity in different cell lines, to determine the effective dose and to better understand the mechanism of action of Ang797 and its analogs in vitro. The proposed in vivo studies will provide important preclinical efficacy data regarding the ability of this Met and Tie2 antagonist to ameliorate RA in animal models. The primary focus of this proposal is the development of small molecules that inhibit SF/HGF/Met and Tie-2 signaling for therapeutic advantage. Our lead compound, Ang797 demonstrates highly innovative approach to the treatment of Rheumatoid Arthritis, with significant clinical potential. ? ? ? ?
