Novel Angiogenesis Inhibitors Targeting the Anthrax Toxin Receptors

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Angiogenesis dependant disease is a major cause of blindness in the developed world, and there remains a generalized outstanding need for broadly active antiangiogenesis therapies which do not inhibit just a single growth factor. We have discovered that anthrax protective antigen mutants (e.g. PASSSR) can powerfully suppress corneal neovascularization induced by multiple growth factors. Our long-range goal is to understand the mechanism by which this suppression is accomplished and develop appropriate therapeutics based on this mechanism. Our working hypotheses is that binding of endogenous ligand(s) to the anthrax toxin receptors (ANTXR1/TEM8 and/or ANTXR2/CMG2) is important in angiogenic processes, and that inhibition of this interaction by competing ligands will inhibit angiogenesis. We will employ several strategies to test this hypothesis. First, we will explain the biochemical mechanism responsible for the observed antiangiogenic activity of PASSSR. We will definitively identify both the specific receptor(s) that mediate the antiangiogenic effect inhibited by PASSSR and the signaling molecule(s) associated with that effect. Second, we will identify small molecule ATR inhibitors and assess their antiangiogenic properties ex vivo. Relevant small molecule inhibitors will be isolated using high throughput screening assays developed as a part of the NIH Roadmap Initiative. The antiangiogenic activity of the identified molecules will then be evaluated in tissue culture. Third, we will assess the ability of isolated ATR inhibitors to inhibit ocular angiogenesis in vivo. Antiangiogenic activity will be evaluated using two mouse models of ocular angiogenesis: the corneal neovascularization model, and a laser-induced choroidal neovascularization model. Successful completion of these studies will both establish the anthrax toxin receptor(s) as appropriate targets for antiangiogenic therapy and provide small molecule lead compounds for broad spectrum antiangiogenic therapies. Pathologies addressed by successful completion of this proposal would thus encompass disorders of ocular angiogenesis such as macular degeneration, diabetic retinopathy, retinopathy of prematurity, and glaucoma, corneal neovascularization associated with conditions such as Herpetic Keratitis, Trachoma, burns, and revascularization of corneal transplants, and other angiogenesis-dependant diseases such as cancer, arthritis, and cardiovascular disease. Hence, these studies are likely to have a significant impact on human health. We have shown that large protein inhibitors of the anthrax toxin receptors can inhibit corneal neovascularization and other angiogenesis-dependant diseases. We seek to understand the mechanism by which this inhibition occurs and identify small molecules with similar activity. These molecules, or similar molecules can then be used to treat corneal neovascularization, and other angiogenesis-dependant diseases (e.g. macular degeneration, diabetic retinopathy, retinopathy of prematurity, cancer, cardiovascular disease, arthritis, etc.).