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AssigneeEnzo Therapeutics, Inc.
InventorsDianqing (Dan) Wu, Dakai Liu, James J. Donegan
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The mechanism by which the high bone mass (HBM) mutation (G171V) of the Wnt coreceptor LRP5 regulates the canonical Wnt signaling was investigated. The mutation was previously shown to reduce Dkk protein-1-mediated antagonism, suggesting that the first YWTD repeat domain where G171 is located may be responsible for Dkk protein-mediated antagonism. However, we found that the third YWTD repeat, but not the first repeat domain, is required for DKK1-mediated antagonism. Instead, we found that the G171V mutation disrupted the interaction of LRP5 with Mesd, a chaperon protein for LRP5/6 that is required for the coreceptors' transport to cell surfaces, resulting in less LRP5 molecules on the cell surface. Although the reduction in the level of cell surface LRP5 molecules led to a reduction in Wnt signaling in a paracrine paradigm, the mutation did not appear to affect the activity of coexpressed Wnt in an autocrine paradigm. Together with the observation that osteoblast cells produce autocrine canonical Wnt, Wnt7b, and that osteocytes produce paracrine Dkk1, we believe that the G171V mutation may cause an increase in Wnt activity in osteoblasts by reducing the number of targets for paracrine Dkk1 to antagonize without affecting the activity of autocrine Wnt.
A method of modulating a pathophysiological process in a subject in need thereof, wherein said pathophysiological process comprises glucose metabolism, cholesterol metabolism, lipid metabolism, triglyceride metabolism, adipogenesis, tumorigenesis, neurogenesis or any bone-related activity, comprising administering to said subject a compound having the following structure (I):
A method for the treatment of a bone fracture, bone disease, bone injury, or bone abnormality in a subject in need thereof comprising administering to said subject a compound having the structure (I):
A method for the treatment of diabetes, hyperglycemia or any metabolic disease in a subject in need thereof comprising administering to said subject a compound having the structure (I):
A method of modulating a pathophysiological process in a subject in need thereof, wherein said pathophysiological process comprises glucose metabolism, cholesterol metabolism, lipid metabolism, triglyceride metabolism, adipogenesis, tumorigenesis, neurogenesis or any bone-related activity, comprising administering to said subject a compound having the structure (II):
A method for the treatment of a bone fracture, bone disease, bone injury, or bone abnormality in a subject in need thereof comprising administering to said subject a compound having the structure (II):
A method for the treatment of diabetes, hyperglycemia or any metabolic disease in a subject in need thereof comprising administering to said subject a compound having the structure (II):
A method of modulating a pathophysiological process in a subject in need thereof, wherein said pathophysiological process comprises glucose metabolism, cholesterol metabolism, lipid metabolism, triglyceride metabolism, adipogenesis, tumorigenesis, neurogenesis or any bone-related activity, comprising administering to a subject a compound having the structure (III):
A method of treatment of a bone fracture, bone disease, bone injury, or bone abnormality in a subject in need thereof comprising administering to said subject a compound having the structure (III):
A method for the treatment of diabetes, hyperglycemia or any metabolic disease in a subject in need thereof comprising administering to said subject a compound having the structure (III):
A method of modulating a pathophysiological process in a subject in need thereof, wherein said pathophysiological process comprises glucose metabolism, cholesterol metabolism, lipid metabolism, triglyceride metabolism, adipogenesis, tumorigenesis, neurogenesis or any bone-related activity, comprising administering to said subject a compound having the structure (IV):
A method for the treatment of a bone fracture, bone disease, bone injury, or bone abnormality in a subject in need thereof comprising administering to said subject a compound having the structure (IV):
A method for the treatment of diabetes, hyperglycemia or any metabolic disease in a subject in need thereof comprising administering to said subject a compound having the structure (IV):
A method of modulating a pathophysiological process in a subject in need thereof, wherein said pathophysiological process comprises glucose metabolism, cholesterol metabolism, adipogenesis, tumorigenesis, neurogenesis or any bone-related activity, comprising administering to said subject a compound having the structure (V):
A method for the treatment of a bone fracture, bone disease, bone injury, or bone abnormality in a subject in need thereof comprising administering to said subject a compound having the structure (V):
A method for the treatment of diabetes, hyperglycemia or any metabolic disease in a subject in need thereof comprising administering to said subject a compound having the structure (V):
A composition for modulating a pathophysiological activity, wherein said pathophysiological activity comprises glucose metabolism, adipogenesis, tumorigenesis, neurogenesis or any bone-related activity comprising a compound having the structure (I):
A composition for treatment of a bone fracture, bone disease, bone injury or bone abnormality comprising a compound having the structure (I):
A composition for treatment of hyperglycemia, diabetes or any metabolic disease comprising a compound having the structure (I):
A composition for modulating a pathophysiological activity, wherein said pathophysiological activity comprises glucose metabolism, cholesterol metabolism, adipogenesis, tumorigenesis, neurogenesis or any bone-related activity comprising a compound having the structure (II):
A composition for the treatment of a bone fracture, bone disease, bone injury or bone abnormality comprising a compound having the structure (II):
A composition for the treatment of diabetes, hyperglycemia or any metabolic disease comprising a compound having the structure (II):
A composition for modulating a pathophysiological activity, wherein said pathophysiological activity comprises glucose metabolism, cholesterol metabolism, adipogenesis, tumorigenesis, neurogenesis or any bone-related activity comprising a compound having the structure (III):
A composition for the treatment of a bone fracture, bone disease, bone injury or bone abnormality comprising a compound having the structure (III):
A composition for treatment of diabetes, hyperglycemia or any metabolic disease comprising a compound having the structure (III):
A composition for modulating a pathophysiological activity, wherein said pathophysiological activity comprises glucose metabolism, cholesterol metabolism, adipogenesis, tumorigenesis, neurogenesis and bone-related activity comprising a compound having the structure (IV):
A composition for the treatment of a bone fracture, bone disease, bone injury, or bone abnormality comprising a compound having the structure (IV):
A composition for the treatment of diabetes, hyperglycemia or any metabolic disease comprising a compound having the structure (IV):
A composition for modulating a pathophysiological activity, wherein said pathophysiological activity comprises glucose metabolism, cholesterol metabolism, adipogenesis, tumorigenesis, neurogenesis or any bone-related activity comprising a compound having the structure (V):
A composition for treatment of a bone disease, bone fracture, bone injury, or bone abnormality comprising a compound having the structure (V):
A composition for treatment of diabetes, hyperglycemia or any metabolic disease comprising a compound having the structure (V):
An isolated compound having the structure (VI):
A compound having the structure (VII):
An isolated compound having the structure (VIII):
A method for identifying a compound that interferes with the binding of protein to LRP5, LRP6, Wnt, Dkk, frizzled, disheveled, beta-catenin or LEF-1/TCF protein comprising
A method for identifying a compound that interferes with the binding of protein to LRP5, LRP6, Wnt, Dkk, frizzled, disheveled, beta-catenin or LEF-1/TCF protein or receptor comprising
A composition selected by the steps of:
A composition selected by the steps of:
Dependencies are inferred from the claim text.