Fox Chase Cancer Center

Dynamis Therapeutics, Inc.

Francis Kappler

Truman R Brown

Annette Tobia

Benjamin S Szwergold

Aqqaluk Peterson

Bangying Su

Sundeep Lal

Disclosed is a class of compounds which inhibit the enzymatic conversion of fructose-lysine into fructose-lysine-3-phosphate in an ATP dependent reaction in a newly discovered metabolic pathway. According to the normal functioning on this pathway, fructose-lysine-3-phosphate (FL3P) is broken down to form free lysine, inorganic phosphate and 3-deoxyglucosone (3DG), the latter being a reactive protein modifying agent. 3DG can be detoxified by reduction to 3-deoxyfructose (3DF), or it can react with endogenous proteins to form advanced glycation end-product modified proteins (AGE-proteins) Also disclosed are therapeutic methods of using such inhibitors to alleviate deleterious effects of 3DG.

Methods for alleviating deleterious effects of 3-deoxyglucosone

The invention relates to a method of removing 3-deoxyglucosone and other alpha-dicarbonyl sugars from skin. The invention further relates to methods of inhibiting production and function of 3-deoxyglucosone and other alpha-dicarbonyl sugars in skin. The invention also relates to methods of treating 3-deoxyglucosone and other alpha-dicarbonyl sugars associated diseases and disorders of skin.

3-deoxyglucosone and skin

The invention relates to the discovery that 3-deoxyglucosone (3DG) and other alpha-dicarbonyl sugars associated diseases and disorders are present and produced in the skin. Further, the invention relates to the discovery that amadorase, an enzyme that mediates 3DG synthesis, is also present in the skin. Thus, the invention further relates to methods of inhibiting production and function of 3-deoxyglucosone and other alpha-dicarbonyl sugars in skin thereby treating or prevention various diseases, disorders or conditions. Additionally, the invention relates to treatment of various diseases, disorders or conditions associated with or mediated by oxidative stress since 3DG induces ROS and AGEs, which are associated with the inflammatory response caused by oxidative stress.

Disclosed is a class of compounds which inhibit the enzymatic conversion of fructose-lysine into fructose-lysine-3-phosphate in an ATP dependent reaction in a newly discovered metabolic pathway. According to the normal functioning on this pathway, fructose-lysine-3-phosphate (FL3P) is broken down to form free lysine, inorganic phosphate and 3-deoxyglucosone (3DG), the latter being a reactive protein modifying agent. 3DG can be detoxified by reduction to 3-deoxyfructose (3DF), or it can react with endogenous proteins to form advanced glycation end-product modified proteins (AGE-proteins). Also disclosed are therapeutic methods of using such inhibitors to treat glycogen storage diseases, including Fanconi's syndrome, as well as other pathological conditions resulting from the formation of AGE-proteins.

Compounds and methods for treating glycogen storage disease and other pathological conditions resulting from formation of age-proteins

The present invention is based on the discovery of a metabolic pathway in which a specific kinase converts fructose-lysine into fructose-lysine-3-phosphate in an ATP dependent reaction. Fructose-lysine-3-phosphate (FL3P) is then broken down to form free lysine, inorganic phosphate and 3-deoxyglucosone (3DG), the latter being a reactive protein modifying agent. 3DG can be detoxified by reduction to 3-deoxyfructose (3DF), or it can react with endogenous proteins to form advanced glycation end-product modified proteins (AGE-proteins), which are believed to be a cause of diabetic complications. Disclosed is a class of compounds which inhibit the action of FL3P kinase in the above-mentioned pathway. Also disclosed are therapeutic methods of using such inhibitors to reduce formation of AGE-proteins and thereby lessen, reduce and delay diabetic complications, as well as methods for assessing a diabetic's risk of developing complications and for determining the efficacy of the disclosed inhibitor therapy by measuring the ratio of 3DG to 3DF in a biological sample following an oral dose of a fructose-lysine-containing food product.

Compounds and methods for therapeutic intervention in preventing

Concentrations of one or more carbohydrates phosphorylated at a secondary hydroxyl, including fructose-3-phosphate and sorbitol-3-phosphate, in biological tissue or cells of diabetic patients are determined by .sup.31 P NMR Spectroscopy, High Performance Liquid Chromatography (HPLC) or other appropriate analytical techniques. Elevated levels of such phosphorylated carbohydrates, relative to a prescribed standard or threshold level, are associated with an increased risk for developing the degenerative complications of diabetes. A method is provided for determining the relative concentrations of such phosphorylated carbohydrates, whereby the relative risk of a patient for the development of diabetic complications and the efficacy of therapeutic intervention in prevention of such complications may be assessed.

Growing community of inventors

Philadelphia, PA, United States of America

Francis Kappler