Fibrosis: Galectin-3 is a carbohydrate-binding protein whose expression has been shown to play a central role in fibrosis development and progression. Specifically, galectin-3 has been linked to a number of biologic processes including inflammation, aberrant cell activation and proliferation (macrophages, neutrophils, and mast cells), fibrogenesis and ultimately, organ dysfunction. Experimental data have implicated galectin-3 in a variety of diseases across a number of organ systems, including liver, kidney, lung, and heart. Notably, blockade of galectin-3 has been shown to prevent and even reverse fibrosis following organ damage making it a promising therapeutic strategy.
Applying our understanding of carbohydrate biology and chemistry, we have rationally-designed several high-potency, selective, small-molecule “glycomimetic” antagonists of galectin-3. These novel compounds have proven anti-fibrotic activity, as demonstrated by attenuated progression of lung fibrosis after bleomycin in an animal model of pulmonary fibrosis. Importantly, and in addition to intravenous or topical administration (e.g. delivered via inhaler to the lungs), we have shown that our galectin-3 antagonists are readily bioavailable following subcutaneous dosing.
Cancer: Current research indicates that galectins have important roles in modulating the immune and inflammatory response to cancer that contributes to neoplastic transformation, tumor cell survival, angiogenesis and metastasis. TIM-3 and LAG-3 are two “checkpoint regulators” that down-regulate the immune system by binding to the galectins to limit the ability of the immune system to recognize, respond and destroy cancer cells.
Using our expertise in carbohydrate chemistry, we have rationally-designed several dual-function antagonists that selectively block the interaction of TIM-3 and LAG-3 with galectin-9 and galectin-3, respectively, in a single molecule. In collaboration with several leading oncology academic institutions, we are testing the ability of these small-molecule galectin-9/galectin-3 antagonists to restore immune anti-cancer function in animal models of disease.
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